The 32-year-old has signed a two-year contract with the Hornets.
He played 202 times for Spurs after joining from Newcastle in August 2016 and played a key role in helping the club to the Champions League final in 2019.
Sissoko becomes the 11th first-team signing for Watford this summer, and will compete for a place in the side with fellow midfield reinforcements Imran Louza, Juraj Kucka, Ozan Tufan and Peter Etebo.
The French midfielder made 202 appearances for Tottenham since joining the club in the summer of 2016 from Newcastle United. He has been capped 71 times by France and was a member of Didier Deschamps squad at Euro 2020.
“He is a very good player and I think he would be very good for us,” Watford boss Xisco Munoz said on Friday.