On 23 June 2010, German club Schalke 04 announced that they had signed Papadopoulos on a four-year deal, keeping him until 2014. On 21 August 2010, Papadopoulos made his Bundesliga debut for the club in a 2–1 loss against Hamburger SV. On 25 August 2011, in the qualification round of the UEFA Europa League, he scored his first goal for Schalke in a 6–1 win over HJK Helsinki. On 1 December, in a group stage game in the Europa League, Papadopoulos scored the opening goal in a 2–1 win over Steaua București. On 17 December, Papadopoulos scored his first goal in the Bundesliga in a 5–0 win over Werder Bremen and scored the next game on 21 January 2012 in a 3–1 win over VfB Stuttgart. Since joining Schalke from Olympiacos, Papadopoulos has played in over 70 matches in all competitions, scoring five goals and has ultimately gathered respect and praise from all over Europe due to his tenacious and skillful defending considering his young age.