[citation needed] During the 2006–07 Super League Greece, Papastathopoulos managed to make 14 appearances whilst competing against the likes of Bruno Cirillo, Traianos Dellas and Vangelis Moras.

[14][15][16] On 21 July 2011, Papastathopoulos moved to the Germany club Werder Bremen on a loan deal until the end of the 2011–12 season, with the option to purchase outright.

[17][18][19] Following impressive performances on loan, on 16 April 2012, it was announced that Papastathopoulos would join Bremen on a permanent basis for a €5 million transfer fee.

In March 2013, in the midst of a relegation battle and with tensions high, Papastathopoulos engaged in a training ground brawl with teammate Marko Arnautović.

"[27] With centre-back Felipe Santana departing Dortmund for Schalke 04, Papastathopoulos began as the effective third-choice behind tandem Neven Subotić and Mats Hummels.

He suffered the injury to his right leg in Dortmund's 1–0 win over Borussia Mönchengladbach, a result that ended a five-match Bundesliga losing streak for the club.

[33] In the summer of 2015, Papastathopoulos was linked with moves to various English Premier League clubs as Dortmund prepared for a new start following long-time manager Jürgen Klopp's departure.

Dortmund Sporting Director Michael Zorc, however, said Papastathopoulos would still have a part to play for BVB in new manager Thomas Tuchel's debut season with the club.

On 22 February 2016, Papastathopoulos missed the second leg of the UEFA Europa League round-of-32 tie against FC Porto and the Bundesliga clash with Bayern Munich due to an adductor injury, as tests confirmed that the 27-year-old would be out for up to three weeks.

The Greek centre back picked up the injury during Dortmund's 1–0 win against Bayer Leverkusen and was replaced 13 minutes from time at the BayArena.

Papastathopoulos looked to be offside as Guerreiro swung in a free-kick from the right, which the Greece defender met with a header planted inside the right-hand post.

On 20 May 2017, Papastathopoulos reached 100 appearances with Dortmund in Bundesliga in a home game against Werder Bremen and secured automatic qualification to the group stage of next season's UEFA Champions League.

[51] On 17 October 2017, after losing its UEFA Champions League opening games in Group H to Tottenham Hotspur and Real Madrid, Dortmund needed a win to kick-start its campaign in Europe's premier club competition, but they succeeded only to seal an away draw against Cypriot champions APOEL, as the Greek defender equalised with a header to Mario Götze's cross.

[55] On 2 July 2018, Arsenal announced that Papastathopoulos had agreed a long-term contract with the club for a reported fee £17.6 million and would wear the number 5 shirt.

On 4 October 2018, Papastathopoulos scored his first for the club, setting the Gunners on their way to a comfortable 3–0 victory over Qarabag in the 2018–19 UEFA Europa League group stage: after just four minutes of play in Baku, the centre-back was left unmarked inside the opposing penalty area, deflecting the ball home after an initial header fell into his path.

[61] On 12 April 2019, Papastathopoulos was named to the UEFA Europa League's 'Team of the week' after playing a vital role in Arsenal's 2–0 win over Napoli in the first leg of the quarter-finals.

[62] On 24 April 2019, Papastathopoulos scored his maiden goal in the English Premier League via a close-range header from a corner kick, but Arsenal slipped to a 3–1 defeat against Wolverhampton Wanderers.

[64] On 27 October 2019, Papastathopoulos – marking his 50th appearance – scored his first goal of the season, after Crystal Palace failed to clear Nicolas Pépé's corner in a 2–2 draw at home.

[65] On 1 January 2020, he scored a close-range finish to seal a 2–0 win over Manchester United, securing Mikel Arteta his first victory in charge of the Gunners.

[72] On 26 October 2023, after leaving Olympiacos at the end of his contract, Papastathopoulos signed a one-year deal with La Liga club Real Betis.

[77] Papastathopoulos became the first player to be sent off at UEFA Euro 2012 during the opening game of the tournament against co-hosts Poland after receiving two yellow cards, following what pundits decried as two poor decisions by referee Carlos Velasco Carballo.

[81] On 11 June 2019, following the loss to Armenia at the Olympic Stadium, Papastathopoulos called for immediate changes to be made to the Greece national squad set-up, and he allegedly requested for Angelos Anastasiadis to be removed from his role of head coach when speaking to EPO president, Evangelos Grammenos.