On 19 December 2015, Papastathopoulos scored his first goal in the 2015–16 Bundesliga in an eventual 2–1 away loss to 1. FC Köln, giving his club the lead in the first-half from a header from a corner. On 30 January 2016, in a league game against Ingolstadt 04, Papastathopoulos reached his 100th Bundesliga appearance with Dortmund. 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. On 21 May 2016, Papastathopoulos featured in his third DFB-Pokal final in a row, putting in a tremendous performance despite a missed penalty, but he did not succeed in winning the DFB-Pokal for first time in his career.