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 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 to the kicker magazin XI of the year.

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

He opened his 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.

International career
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.