The Irishman injured his knee against Aston Villa last week and will not recover until the summer break, with Sergio Reguilon starting at left wing-back in the only change against Brighton this afternoon.
“I think the first visit with the doctor said he can recover without surgery,” Spurs boss Antonio Conte said. “Seven to eight weeks before he recovers. For this reason, his season has finished.
“This is really bad news for us. We know very well the improvement in our team and it’s a pity to lose a player like him for the rest of the season.”
Midfielder Oliver Skipp is still out injured, as is Japhet Tanganga, but Ryan Sessegnon is at least now back available.
Sessegnon has been battling with a hamstring injury and makes the bench this afternoon.
Tottenham starting XI: Lloris; Romero, Dier, Davies; Royal, Hojbjerg, Bentancur, Reguilon; Kulusevski, Kane, Son.
Subs: Gollini, Sessegnon, Rodon, Lavinier, Sanchez, Winks, White, Bergwijn, Moura.
Saturday 12.30pm BST, BT Sport
Venue: Tottenham Hotspur Stadium
Referee: Craig Pawson
Out: Tanganga (knee), Skipp (pelvis), Doherty (knee)