Before joining the youth team of VfB Stuttgart in 1995, he played at TV Oeffingen. In the first months of the 2006–07 season, he was called up into VfB’s Bundesliga squad by manager Armin Veh. His debut followed on 1 October 2006 against Hertha BSC, replacing Antônio da Silva at the end of the 2–2 away draw. He scored his first two goals on 29 October in the 3–0 win against Schalke 04 at the Mercedes-Benz-Arena. On 29 January 2007 he signed his first professional contract at VfB, valid until June 2009. In the last game of the season on 19 May, Khedira scored the winner as Die Schwaben came from behind to defeat Energie Cottbus 2–1 and became champions for the first time in 15 years.

On 9 July 2008, he extended his contract until the summer of 2011. In the ensuing season, he scored a career-best 7 league goals in 27 games, including both in a 2–2 draw against Bayern Munich on 13 December.

Khedira made his debut for the senior national squad on 5 September 2009 in a friendly match against South Africa. He was substituted on in the 73rd minute for Simon Rolfes.

On 30 July 2010, Khedira moved to Real Madrid for an undisclosed fee, signing a contract until 2015. Khedira made his debut on 13 August in a friendly match against Bayern Munich, which Real Madrid won 4–2 on penalties for the Franz-Beckenbauer-Cup. His league debut came sixteen days later, in a 0–0 away draw against Mallorca. He made 40 appearances across his first season in Spain and won his first club honour on 20 April 2011 as his team won the Copa del Rey final against El Clásico rivals FC Barcelona.

Khedira was called up to the German squad for the 2010 World Cup in South Africa by coach Joachim Löw. Filling in for the injured Michael Ballack as a central midfielder, he played in all seven matches, and was only substituted twice, as Germany reached the semi-finals. After appearances in five friendlies prior to the World Cup, he made his first competitive appearance against Australia in Germany’s first group game. On 10 July 2010, with his first senior international goal, he scored Germany’s 16th and last goal of the tournament, in the third place match against Uruguay; Khedira’s match-winning header, which came eight minutes from time, ensured the final 3–2 scoreline, and won the young German team the bronze medal.

He scored his first competitive goal for Real Madrid in the Champions League, on 18 October 2011 against Olympique Lyonnais. He scored his first Copa del Rey goal against Málaga CF in a 3–2 home win when Real Madrid were trailing behind 0–2, and his first league goal against RCD Espanyol in a 5–0 home win.

On 21 April 2012, Khedira scored his second league goal, against Barcelona; the goal was Real Madrid’s 108th of the season in the league, breaking the previous La Liga record of 107, also set by them in the 1989–90 season.

Khedira tore his ACL in his right knee in a friendly match against Italy on 15 November 2013 and it was estimated that he would be ruled out for around six months, which put his participation at the 2014 FIFA World Cup into question. However, he recovered in time to be named in Germany’s squad for the tournament, and was selected to start in the team’s opening match, a 4–0 win against Portugal. On 8 July, he scored Germany’s fifth goal in the 7–1 semi-final defeat of hosts Brazil. He was injured during the pre-match warmup for the Final against Argentina, and was replaced by Christoph Kramer in the team’s starting line-up, as Germany eventually won 1–0 after extra time.

Khedira is considered a dynamic and well-rounded midfielder, with good awareness and “flawless aerial ability”, who can cover a lot of ground efficiently, recover the ball and quickly join in the team’s attacking plays; he is also capable of being a goal threat with his heading accuracy and powerful mid-range shooting. A physically strong, energetic, and tactically intelligent player, he is also known for his ball-winning abilities, work-rate, and vision, as well as his solid technique and reliable passing, which allow him to play anywhere in midfield; although usually a central midfielder, he has also been deployed as a defensive midfielder, as a box-to-box midfielder, or even in a more offensive role as a mezzala, due to his stamina, movement (both on and off the ball), positional sense, and versatility, which also enable him to create space or contribute to his team’s offensive plays with goals, due to his ability to make late runs into the penalty area from behind. Jonathan Wilson, when writing for The Guardian in 2013, described Khedira as a “destroyer with carrying tendencies,” namely a holding midfielder who is predominantly tasked with running, winning back possession, and distributing the ball to other players, but who is also “capable of making late runs or carrying the ball at his feet.” In spite of his playing ability, however, Khedira is also known to be injury-prone.

On 9 June 2015, Italian side Juventus announced that Khedira had signed a four-year deal on a free transfer. The move was completed on 1 July, at the start of the 2015–16 season.

On 20 March 2016, Khedira scored his fourth goal of the league season in a 4–1 win at Torino in the Derby della Mole, but was given a straight red card for dissent later on.

On 20 August 2016, Khedira opened the 2016–17 Serie A season with a goal in a 2–1 home win over Fiorentina. A week later he scored the only goal in a 1–0 away win over Lazio in the league.

On 22 October 2017, Khedira scored his first career hat-trick in a 6–2 away win over Udinese.

On 7 March 2018, Khedira made his 100th appearance for Juventus in a 2–1 win over Tottenham at Wembley Stadium, in the second leg of the round of 16 of the UEFA Champions League, assisting Gonzalo Higuaín’s goal.

In September 2018, Khedira signed a new contract with Juventus, which would keep him at the team until 2021. In February 2019 he was ruled out for a month to undergo treatment after it was diagnosed that he suffered from an irregular heartbeat. He returned to action on 6 April, coming as a substitute for his injured compatriot Emre Can in a 2–1 home win over Milan.

On 4 June 2018, Khedira was included in Joachim Löw’s final 23-man squad for the 2018 FIFA World Cup. As Germany were eliminated in the group stage, Khedira was deemed as one of the weakest performers in the squad. After the tournament, he was left off the team for the subsequent UEFA Nations League matches.