In March 2007, Medel made his international debut for Chile in a friendly against Argentina. Later that year, he played a key role in Chile’s third-place finish in the U-20 World Cup held in Canada. He was sent off in the semi-final match against Argentina, when he kicked Gabriel Mercado in the 24th minute and was suspended for the third-place play-off. Medel claimed that he was tasered by police after the match.

On 20 July 2009, he joined Boca Juniors on an initial loan for US$300,000 with the option to buy for $2.5 million, with Damián Díaz being sent in the opposite direction. Medel said of the move “This is a dream come true. It is a very important club, and one which has players which I admire a lot, Juan Román Riquelme, Martín Palermo and Sebastián Battaglia. He is my idol and has me very happy to play by his side”. Medel scored both goals in a 2–0 win in the Superclásico against River Plate on 25 March 2010.

He made his competitive debut for Chile in the 2010 FIFA World Cup qualification match against Bolivia in a 2–0 victory at the Estadio Hernando Siles in La Paz, scoring both goals, the first being a bicycle kick. Medel played an important role in Chile’s qualification for the 2010 FIFA World Cup, playing as a central defender or right back. He started in the three group-stage matches at the World Cup finals in South Africa, but was suspended for the round of 16 match against Brazil, where la Roja were eliminated.

Medel joined Sevilla for €3 million on 28 January 2011, on a 4½-year contract, on the same day as the club also signed Ivan Rakitić for their central midfield. He said “I am happy to be here, I hope that everything goes well. I’m a player who puts a lot into my heart on the pitch, I hope that with my playing that I can contribute to Sevilla”.

On 11 August 2013, Cardiff City confirmed that they had signed Medel from Sevilla for a club record £11 million fee on a four-year deal. He made his debut for the club on 17 August, in a 2–0 defeat against West Ham United. He made his home debut at the Cardiff City Stadium on 25 August, in a 3–2 win against Manchester City. Medel played all 90 minutes and received the fans’ man of the match award.

After Cardiff’s relegation, Medel joined Italian club Inter Milan for a reported £10 million fee on 9 August 2014. The fee, which was £1 million less than what Cardiff had signed Medel for, was criticised by former striker Nathan Blake, but was justified by Cardiff manager Ole Gunnar Solskjær. Medel made his Serie A debut for Inter on 31 August as they began the season with a goalless draw at Torino, playing the full 90 minutes.

Medel played a key role in 2014 FIFA World Cup qualification, scoring the goal that secured qualification for the 2014 FIFA World Cup, heading a goal against Ecuador. Medel captained Chile in a 1–0 friendly defeat to Germany on 5 March 2014. He was one of 23 players who were called up by coach Jorge Sampaoli to play in 2014 FIFA World Cup in Brazil. Medel played as a starter alongside Gonzalo Jara in the center of defence, for Chile who beat Australia 3–1 in Cuiabá to get first three points of the World Cup campaign. He also played a full 90 minutes in second match against current world champions Spain, with Chile getting a historic 2–0 win. Spain’s loss sealed the qualification of both Chile and the Netherlands to the knockout stage, and eliminated both Spain and Australia. Spain became the fifth defending champions to be knocked out in the group stage. Medel played 90 minutes in the final group match against the Netherlands who won 2–0 and won the group, while Chile finished Group B as runner-up with six points. Chile were eliminated in the round of 16 against the same team that eliminated them in last tournament, Brazil, but this time, Brazil advanced to the quarter-finals by winning on penalty shootout.

On 31 October 2015, Medel scored his first goal for Inter to give the Nerazzurri a 1–0 victory over Scudetto rivals Roma at the Stadio Giuseppe Meazza.

At the 2015 Copa América, held in Chile, Medel scored during a 5–0 win against Bolivia which ensured that La Roja would progress to the knockout stage as Group A winners. In the semi-final against Peru, he scored an own goal from Luis Advíncula’s cross to equalise, but Chile advanced to the final winning 2–1. In the final against Argentina, Medel played as a starter and helped the team to win the trophy on penalty kicks, after the regular time ended in a goalless draw. Medel became the fourth most capped player with 80 matches, equaling his defence partner Gonzalo Jara. That was Medel’s first major trophy with Chile. For his performances he was named in the Team of the tournament.

Medel usually plays as a defensive midfielder; however, he is also capable of playing as a defender, and has even been deployed as a centre-back throughout his career, as well as in other midfield roles. Due to his work-rate, physicality, tenacity, tactical intelligence, and his aggressive, hard-tackling style of play, as well as his leadership on the pitch, he is nicknamed Pitbull. In 2015, manager Roberto Mancini described Medel as a warrior.

On 23 October 2016, in the 2–1 away defeat at Atalanta, Medel hit Jasmin Kurtić in the face with his left arm, an incident that was not spotted by the referee. A day later, however, he was banned for three league games by Lega Serie A after examining TV images.

On 20 November 2016, in the Derby della Madonnina against cross-town rivals A.C. Milan, Medel played as centre-back for 37 minutes before replaced by Jeison Murillo due to a knee injury. Following the match, which ended in a 2–2 draw, it was confirmed that Medel had damaged his lateral meniscus and would be sidelined until January 2017.

On 11 August 2017, Medel signed for Turkish Süper Lig champions Beşiktaş for a reported €3 million. He signed a three-year contract.

In June 2017, Medel was named in the 2017 FIFA Confederations Cup squad in Chile’s first ever participation. On 13 June, in the friendly against Romania, Medel received a red-card in 33rd minute as Chile slumped into a 3–2 away defeat. It was his fourth red-card with the national team in 99 appearances. He captained Chile in the first two Group B due to Claudio Bravo’s injury, respectively in the matches against Cameroon and Germany, also earning his 100th cap in the process, becoming the fourth Chile player to achieve the feat. Then he was rested for the final group match as Chile achieved a second-place which allowed them to go to knockout stage.

On 29 August 2019, Medel signed a three-year contract with Serie A club Bologna for a reported fee of €2.5 million. He debuted for Bologna against rivals SPAL on 30 August 2019.