The Argentine, 47, was appointed in May 2014 and led the club to the Champions League final last season, where they lost to Liverpool in Madrid.
But Spurs have made a disappointing start to the current campaign and are 14th in the Premier League.
“We were extremely reluctant to make this change,” said Spurs chairman Daniel Levy.
“It is not a decision the board has taken lightly, nor in haste. Regrettably domestic results at the end of last season and beginning of this season have been extremely disappointing.
“It falls on the board to make the difficult decisions – this one made more so given the many memorable moments we have had with Mauricio and his coaching staff – but we do so in the club’s best interests.”
Pochettino’s assistant Jesus Perez, and coaches Miguel d’Agostino and Antoni Jimenez have also left the club.
Tottenham said in a statement that they would provide an update on new coaching staff “in due course”.