Sissoko began his football career playing for local youth clubs in the Île-de-France region, such as Espérance Aulnay and AS Red Star 93. In 2002, he moved south to join professional club Toulouse. Sissoko spent four years in the club's youth academy and made his professional debut in the 2007–08 season. He also played in the UEFA Champions League for the first time. In the following season, Sissoko earned award nominations for his performances and also helped Toulouse qualify for the newly created UEFA Europa League. He eventually joined Newcastle United in the Premier League in 2013, before moving on to Tottenham Hotspur in 2016 after Newcastle's relegation from the top flight. At Tottenham, Sissoko finished runner-up in the 2016–17 Premier League and the 2018–19 UEFA Champions League.