Großkreutz began his career with the Dortmund clubs DJK Rot-Weiß Obereving, VfL Kemminghausen and FC Merkur 07. In 2002, he joined Borussia Dortmund, where he played until he moved to Rot Weiss Ahlen. Promoted to first team in 2006, he led the club to promotion to the 2. Bundesliga in 2008. He scored 12 goals and was named in the German sports magazine’s kicker XI of the year.

He opened his account with Dortmund on 5 December 2009 in a 4–0 victory over 1. FC Nürnberg. Sven Bender provided him with a diagonal pass that Großkreutz tucked past Alexander Stephan in goal to give Dortmund a 1–0 lead on eight minutes.

Großkreutz opened his goalscoring account for the new season on 22 September 2010, finishing a nice play as Dortmund thrashed 1. FC Kaiserslautern 5–0. In the following round of fixtures, Dortmund faced promoted side FC St. Pauli at the Millerntor-Stadion in Hamburg. Großkreutz scored two goals on either side of a Shinji Kagawa strike as Dortmund won 3–1 with Großkreutz being named man of the match. On 29 November 2010, Großkreutz signed a four-year contract extension to stay with Dortmund until July 2014. He was involved in all three goals on 14 January 2011, scoring two and providing an assist for Mario Götze, as Dortmund defeated Bayer Leverkusen 3–1 at the BayArena. Großkreutz had a phenomenal second season with Dortmund, netting eight goals and managing seven assists as die Borussen lifted the Bundesliga title.

Großkreutz made his full international debut in a friendly match against Malta on 13 May 2010, helping set up striker Cacau for one of his two goals in a 3–0 win. He next appeared for Germany as a starter against Sweden in a 0–0 draw on 18 November 2010.

Großkreutz figured in Borussia Dortmund’s 4–2 victory over Bayern Munich on 27 July 2013, at BVB’s Signal Iduna Park, Dortmund to lift the 2013 DFL-Supercup.

On 11 December 2013, Großkreutz scored the winning goal away to Marseille in a 2–1 UEFA Champions League win to qualify Dortmund for the knockout phase.

In June 2014, he was named in Germany’s squad for the 2014 FIFA World Cup. Germany went on to win the tournament, though Großkreutz did not make any appearance during the competition.

From April to August 2015, Großkreutz was demoted to Borussia Dortmund II, for whom he played 6 times in lower divisions. In September 2015 he was sold to Galatasaray. However, the deal was not completed before the closure of the transfer window.

On 2 September 2015, it was announced by FIFA that Galatasaray had failed to submit the relevant documentation for Großkreutz before the transfer window closed. FIFA dismissed the case, because the signed documentations were not submitted on time by Galatasaray. FIFA have refused to sanction Großkreutz’s proposed move from Borussia Dortmund to Galatasaray, therefore the player was not eligible to play any matches until 1 January 2016. Großkreutz signed a 3-year contract worth an average of an approx. €1.6 million per season, plus €20,000 per match bonus. Dortmund received a €1.5 million transfer fee and an extra €250,000 if Galatasaray qualified for the UEFA Champions League.

On 6 January 2016, having not made a single competitive appearance for Galatasaray, Großkreutz returned to Germany to join VfB Stuttgart for an approx. €2.2 million.

On 3 March 2017, the contract of Großkreutz was mutually terminated hours after he got into a bar fight. Großkreutz said in a statement on the club website that he “made a mistake” and he wants “nothing to do with football for the time being.”

In April 2017, one month after his departure from VfB Stuttgart, Großkreutz signed with 2. Bundesliga club SV Darmstadt 98 for the 2017–18 season until 2019. He gave his pre-season debut in a warm-up fixture against SG Modau on 23 June 2017.

On 5 July 2018, Großkreutz joined KFC Uerdingen 05. His contract was terminated by the club in October 2020.