De Zerbi became available after leaving Marseille by mutual consent in February, and Tottenham moved quickly after parting ways with interim boss Igor Tudor on Sunday, following just seven games and 44 days in charge.
The north Londoners sit just one point above the relegation zone with seven matches left, having failed to win a league game in 2026.
“I am delighted to be joining this fantastic football club, which is one of the biggest and most prestigious in the world," De Zerbi said.
“In all my discussions with the Club’s leadership, their ambition for the future has been clear – to build a team capable of reaching great achievements, and to do that playing a style of football that excites and inspires our supporters.
"I am here because I believe in that ambition and have signed a long-term contract to give everything to deliver it.
“Our short-term priority is to climb the Premier League table, which will be the complete focus until the final whistle of the last game of the season. I’m looking forward to getting out on the training pitch and working with these players to achieve that.”
De Zerbi established a positive reputation for himself in England during two years as Brighton boss between 2022 and 2024.
He guided the Seagulls to European football for the first time in their history, as well as an FA Cup semi-final in 2023.
A short tenure followed at Marseille, with the 46-year-old recording a second-placed Ligue 1 finish in his one full season in charge.
The Italian returns to England with Spurs on a 'long-term' contract.
Tottenham have not tasted life outside the top flight of English football since 1977-78.
Despite boasting a new 63,000-capacity stadium, state-of-the-art training ground and revenues that make them among the top 10 richest clubs in world football, they are at severe risk of a humiliating relegation to the Championship.
Just a few years ago, they were Champions League regulars under former manager Mauricio Pochettino, reaching the final in 2019.
Tottenham, then managed by Ange Postecoglou, ended their 17-year trophy drought by winning the Europa League last season.
But the warning signs of a battle for survival were there as Postecoglou was dismissed despite victory over Manchester United in the Europa League final after finishing 17th in the Premier League.
Thomas Frank was appointed as the Australian's successor, but the Dane was sacked in February after a run of two wins in 17 league games.
De Zerbi's first game as Spurs boss will come at Sunderland on April 12th.