The 26-year-old has signed a five-year contract with the Serie A champions, with the agreement understood to include a 10 per cent sell-on clause. Inter had identified Spence as an alternative to Denzel Dumfries, who joined Real Madrid just recently, after failing to reach an agreement with Al Ittihad for Moussa Diaby.
Spence was given permission to travel to Italy for a medical on Friday before the two clubs finalised the deal. His departure had been expected after Tottenham strengthened their options at full-back, with Pedro Porro remaining the first-choice right-back and Andy Robertson arriving from Liverpool.
Head coach Roberto De Zerbi had previously indicated that he wanted to keep Spence, but the England defender was no longer considered central to his plans. De Zerbi recently described Porro as the "best in the world" in his position.
Spence leaves Spurs having made 85 appearances for the club after joining from Middlesbrough in 2022. His biggest achievement came during the 2024-25 season, when he helped Tottenham win the Europa League.
His final campaign in England was particularly significant on the international stage. Spence played in all eight of England's matches at the 2026 World Cup as Thomas Tuchel's side finished third, starting the semi-final defeat by Argentina and the victory over France in the third-place play-off.
The move also gives Spence a return to Italy, where he previously spent six months on loan with Genoa in 2024.
Spurs' decision to sell comes despite Spence having three years remaining on his contract, with an option for another season. His performances for England at the World Cup increased his value and helped make the transfer possible.
Shortly before the move was officially confirmed, Spence posted an emotional farewell message to Tottenham supporters.
"A special chapter comes to an end," he wrote. "It's been some journey, with plenty of memories, moments and experiences that I'll carry with me forever, especially that night in Bilbao.
"Thanks to all the staff members who've helped me along the way, the players who've become family and most importantly thank you to the fans. Time for a new chapter now, but Spurs will always have a place in my heart."