The 25-year-old Denmark international has signed a long-term contract with Spurs for an undisclosed fee.
"I think there's a fantastic future ahead for the Club and I wanted so much to be a part of that," he told the club's official website.
Hojbjerg made 109 Premier League appearances in his four seasons with Saints and captained them from December 2018 until June this year.
In a separate move Spurs defender Kyle Walker-Peters has moved to Southampton on a five-year deal.
The right-back has returned to the south-coast club for an undisclosed fee following a successful loan spell last season.