The Spurs captain left the field in tears in the 70th minute after colliding with goalkeeper Antonin Kinsky following a shove from Sunderland striker Brian Brobbey. Kevin Danso replaced him as Roberto De Zerbi's debut as Tottenham manager ended in defeat and the club dropped into the relegation zone.
Tests have confirmed a partial tear of Romero's medial cruciate ligament, reports the Daily Mail. Surgery is not required, but a recovery period of five to eight weeks rules out any involvement in the final six Premier League games. With Tottenham sitting two points adrift of safety, the timing is devastating.
De Zerbi had already flagged the loss of Mohammed Kudus to a quad injury before Sunday's game. Now he faces the run-in without his captain and most experienced defender.
After the defeat at the Stadium of Light, De Zerbi left little doubt about what Romero means to this squad. "He's a crucial player for us," he said. "A good guy, good player, top player, big personality and we need him to finish the season and to achieve our goal."
There are questions too about whether Romero has worn a Spurs shirt for the last time. Persistently linked with a summer exit, the 27-year-old is expected to seek a move away should the club be relegated to the Championship.
The injury recovery timeline does offer a sliver of hope on the international front. Reports from Argentina suggest he could be fit in time for the World Cup, with holders Argentina opening their campaign against Algeria in June. The five-to-eight-week window makes that feasible, though Spurs have been careful not to confirm those projections.
West Ham's 4-0 win over Wolves on the same afternoon compounded Tottenham's misery and nudged Spurs into the bottom three on goal difference. With Brighton next up at home, De Zerbi needs a response immediately — and he must find it without the one player he had counted on to lead it.