In May 2010, Mensah was called up to the Ghana squad for the FIFA World Cup in South Africa. He was eventually named in the 23-man squad. Mensah captained Ghana for the first time in the tournament, starting the whole game and helped the national side win 1–0 against Serbia. Mensah later captained Ghana to an impressive quarter-final finish at the 2010 World Cup, where "the Black Stars" were eliminated on penalties by Uruguay following a 1–1 draw after extra time, in which he took the third penalty with his team, but it was saved by the opposition keeper, Fernando Muslera. A year later on 8 September 2011, Mensah scored his first goal for Ghana, in a 2–0 win against Sudan.