Iniesta burst on to the international scene in 2001, helping Spain win the UEFA European Under-16 Championship. After representing his country at the 2001 FIFA U-17 World Championship held in Trinidad and Tobago, he was in the squad that claimed the UEFA European Under-19 Championship the following year. From then, he became a regular choice for youth coach Juan Santisteban. In 2003, he was part of the side that reached the FIFA World Youth Championship final in the United Arab Emirates, and was named in the FIFA all-star team. During his spell with the Spain U21 side, Iniesta was named captain on several occasions.

In the 2004–05 season, Iniesta featured in 37 out of 38 league games—more than any other player—although 25 of these were substitute appearances. He scored twice as Barcelona won La Liga. An injury to Xavi at the start of the 2005–06 season allowed Iniesta more regular starts in the centre of midfield, and he continued to improve and develop. He played in 11 UEFA Champions League games, including a half-time appearance in the 2006 final, to replace Edmílson. His contribution to the team was praised by manager Frank Rijkaard as Barcelona won a league and Champions League double.

Iniesta was called up to represent the senior Spain squad at the 2006 FIFA World Cup on 15 May 2006, much to the surprise of many. He won his first cap for La Furia Roja when he was brought on at half-time in a friendly against Russia on 27 May. His first goal followed in a friendly against England on 7 February 2007. His long-range effort, hitting the underside of the crossbar on the way in, gave Spain the lead on 63 minutes. Iniesta played a pivotal part in Spain’s qualification for UEFA Euro 2008 by scoring goals against Sweden and by assisting the strikers.

With the departure of Ludovic Giuly ahead of the 2007–08 campaign, Iniesta was able to switch his number 24 shirt for his preferred number 8. Despite rumours of a possible transfer before the season, he extended his contract to 2014 on 25 January 2008, with his buy-out clause being raised to €150 million. Don Balón, a member of European Sports Magazines, named Iniesta one of the most consistent performers in the previous two seasons of La Liga; he placed fifth in 2006–07 and fourth in 2007–08. He also placed ninth in the 2008 FIFA World Player of the Year voting, gaining 37 total points.

At the start of the 2008–09 season, in September 2008, Iniesta was elected the fourth-choice captain behind, in order of preference, Carles Puyol, Xavi and Víctor Valdés; all four were products of the Barcelona youth system. His performances throughout the season were highly lauded, and he received standing ovations both in Barcelona at the Camp Nou, as well as from rival supporters in away matches. A leg injury sustained in mid-November 2008 left Iniesta sidelined until 3 January; initially expected to return to action in six weeks, he did not want to come back until he was 100 percent. Upon his return to action, as a 65th-minute substitute against Mallorca, he scored a crucial goal after just ten minutes on the pitch and completed a Barcelona comeback in front of the Camp Nou.

Iniesta is married to Anna Ortiz; the couple began dating in 2008 and wed on 8 July 2012. They have two daughters, Valeria (born April 2011) and Siena (born May 2017), and a son, Paolo Andrea (born May 2015). They lost an unborn child, son Andrés Jr., due to miscarriage in March 2014. Iniesta is a Catholic.

Barcelona won a second successive league title in the 2009–10 season, securing a record 99 points. Individually, however, Iniesta endured a campaign largely disrupted by recurring injuries. He missed pre-season fitness training due to the thigh tear suffered in the 2009 Champions League final. Despite featuring in almost as many matches as the previous season, he did so mostly as a substitute, starting only 20 games throughout. His season came to a premature end in April after he aggravated a previous calf injury during training.

A contributing factor of Iniesta’s fractured season were the episodes of psychological instability he suffered privately following the death of his close friend Daniel Jarque, a fellow footballer, in August 2009. Even when physically fit, he was often unable to complete training sessions or exert himself. After seeking psychological help, he experienced catharsis when he scored Spain’s match-winning goal in the 2010 FIFA World Cup final, which he dedicated to Jarque by revealing the message “Dani Jarque, always with us” written on his undershirt. “I did it because I felt it deeply,” Iniesta said at the time. “It showed that what is more important than rivalry, your team or your colours is to be human and a good person. I am delighted because it was the most important moment in my career.” Regarding the recurrent injuries that plagued his season, he said, “It was hard, but I will start with more desire than ever.”

Iniesta was selected in Spain’s squad for UEFA Euro 2008 in Austria and Switzerland. Though a stomach ailment somewhat hampered his performances in the group stages, he still played an integral part in the midfield. He played in the first two of Spain’s group stage matches and proved an important part of the team, providing a pass for David Villa’s second goal against Russia. He was not rested, unlike most of Spain’s regulars, for the final group game against Greece, which Spain won 2–1 thanks to a volley from Rubén de la Red and a late winner from Daniel Güiza. Iniesta returned for the quarter-final as Spain beat Italy on penalties; he was substituted before the penalty shootout itself. In the semi-final against Russia, he played the entire 90 minutes and produced a cross that Xavi converted to open the scoring in an eventual 3–0 victory; he was subsequently named the Man of the Match. He played the duration of the final in Spain’s 1–0 win over Germany. Iniesta was named in the Team of the Tournament alongside fellow Spain midfielders Xavi, Marcos Senna and six other teammates. Iniesta did not participate in the 2009 FIFA Confederations Cup in South Africa due to a thigh muscle injury; Spain was eliminated from the tournament at the semi-final stage.

Iniesta was selected for Spain in the 2010 World Cup and scored the second goal in a 2–1 group stage win against Chile. He was also named man of the match. For his excellent performances in helping Spain reach the final of the tournament, Iniesta was shortlisted for the Golden Ball award. During the final, he scored the winning goal in the 116th minute of a 1–0 win against Netherlands. He earned a yellow card for removing his jersey during his ecstatic goal celebration to reveal his message to his late friend Dani Jarque. He won the man of the match award for his performance in the final, which gave Spain its first-ever World Cup.

Much like other Barcelona youth products such as Pep Guardiola, Xavi and Iván de la Peña, Iniesta is a playmaker who relies on his technique, exceptionally precise, creative, and intelligent passing, intuition, movement, and inventiveness to control the midfield, dictate the ebb and flow of play, and create chances or space for teammates. Iniesta has been praised for his understanding and interplay with Xavi; former Barcelona teammate Giovanni van Bronckhorst said of the pair, “They have a special relationship, they always have, they just seem to know where the other one is.” Despite not being particularly prolific in front of goal, during his maturation as a player, he has gained a reputation of a big-game player for club and country, assisting a goal in each of the 2009, 2011 and 2015 UEFA Champions League finals, as well as scoring the winner in the 2010 World Cup Final, not to sideline his vital contributions in the 2006 Champions League Final, the 2008 Euro Final and the 2012 Euro Final. He is also the only footballer in history to win the Man of the Match award in a World Cup Final, a Euro Final & a Champions League Final.

In 2011, Iniesta invested €420,000 in his boyhood club, Albacete, thus becoming its major shareholder. Two years later, with the club facing administrative relegation to the fourth tier of Spanish football, he loaned them a further €240,000 to cover unpaid wages.

Iniesta signed a new contract with Barcelona in December 2013, keeping him at the club until 2018. As vice-captain, he regularly captained Barça throughout the club’s second treble-winning campaign of the 2014–15 season, and became captain after Carles Puyol’s retirement and Xavi’s departure. Iniesta scored three times during the team’s Copa del Rey campaign, and was man of the match in the 2015 UEFA Champions League Final, having assisted Ivan Rakitić’s opening goal in the 3–1 defeat of Italian champions Juventus at Berlin’s Olympiastadion. Their European victory made Barcelona the first club in history to win the treble of domestic league, domestic cup and European Cup twice; Iniesta was among the seven players to have been a part of both treble-winning teams.

At the 2013 FIFA Confederations Cup, Iniesta was named in the Team of the Tournament and awarded the Silver Ball for the second best player in the competition, as Spain finished runner-up to host nation Brazil. Iniesta started all three matches for Spain at the 2014 World Cup, winning his 100th cap in the team’s final group match against Australia. At the UEFA Euro 2016, he assisted the only goal of the match against Czech Republic and put in a man of the match display to give Spain a winning start in the tournament. He started in all four Spain’s matches and were later knocked out by Italy in the Round of 16.

Iniesta had a sponsorship deal with sportswear company Nike, and has appeared in Nike commercials alongside Cristiano Ronaldo, Neymar, Zlatan Ibrahimović and Wayne Rooney. Iniesta features in EA Sports’ FIFA video game series, and was the sixth-highest rated player in FIFA 15. Iniesta’s signature move, La Croqueta, features in FIFA 19. In March 2015, Iniesta had the ninth highest social media rank in the world among sportspeople, with 24 million Facebook fans. On 22 October 2018, Iniesta signed a new sponsorship deal with Japanese sportswear company Asics, with his first signature boot being released on 15 July 2019.

He signed a lifetime contract with Barcelona on 6 October 2017, effectively keeping him with the club for the remainder of his career. He played the 650th game of his career for Barcelona against Levante on 7 January 2018, he was replaced by André Gomes after 76 minutes as the game ended 3–0 in favour of Barcelona.

Despite signing a lifetime contract, on 27 April 2018, Iniesta announced he would be leaving Barcelona by the end of the season. He made his 674th and final appearance for Barcelona on 20 May, in the final league match of the season, a 1–0 home victory over Real Sociedad, as Barcelona celebrated the victory of their 25th league and 30th Copa del Rey title; he came off in the 81st minute for Paco Alcácer.

On 24 May 2018, Japanese club Vissel Kobe announced the signing of Iniesta on a three-year deal. He made his debut on 22 July, coming on as a second-half substitute for Kazuma Watanabe in a 0–3 defeat against Shonan Bellmare. On 11 August 2018, Iniesta scored his first goal in the J1 League in a 2–1 win over Jubilo Iwata.

In May 2018, Iniesta was named in Spain’s squad for the 2018 FIFA World Cup in Russia. He started in all three matches of the group stage, making an assist for Isco in the 2–2 draw against Morocco on 25 June 2018. He came off the bench in the 67th minute in Spain’s last match at the tournament against Russia on 1 July 2018 for the round of 16. After the loss in the penalty shoot-outs, Iniesta announced his retirement from international duty. He amassed 131 senior international caps for Spain and at the time of retiring was the nation’s fourth-most-capped player of all-time, behind only Iker Casillas, Xavi, and Sergio Ramos.

In May 2018, Iniesta revealed to Risto Mejide that he suffered from depression before the 2010 FIFA World Cup due to his injuries and the death of Daniel Jarque.

On 21 December 2019, he scored the opening goal in a 3–1 win over Shimizu S-Pulse in the semi final of the 2019 Emperor’s Cup. On 1 January 2020, he won his first trophy in Japan, starting in Vissel Kobe’s 2–0 victory over Kashima Antlers in the final of the 2019 Emperor’s Cup.