The 26-year-old returned to the starting XI against the Blues after recovering from a toe injury, but his race was run after just 15 minutes of the London derby at the Tottenham Hotspur Stadium.
Romero appeared to injure himself when completing a backheel, and the Argentina international was replaced by Radu Dragusin with Spurs 2-0 up thanks to Dominic Solanke and Dejan Kulusevski's goals.
Following Romero's withdrawal, in addition to Micky van de Ven and Brennan Johnson being forced off, Spurs let their 2-0 lead slip as Chelsea triumphed in a seven-goal spectacular, condemning the Lilywhites to back-to-back losses after their midweek defeat at Bournemouth.
Ange Postecoglou told the press after the game that he had no indication how serious Romero's issue was, but he was more concerned about the South American than he was Johnson and Van de Ven.
Romero out until late January with muscle injury?
Now, journalist Gaston Edul on X claims that Romero will be absent for six weeks with his new muscular problem, although is not related to his previous toe concern, which he has fully recovered from.
The former Juventus and Atalanta BC man could therefore be missing until late January while he recuperates from his newest issue, diminishing Postecoglou's defensive resources even further at a crucial time.
Romero has already sat out seven matches in all tournaments this season, and Spurs have only won three matches when he has been absent, drawing twice and being defeated in the other two.
Dragusin should enjoy another run in the first team while Romero recovers, but Postecoglou is optimistic that Van de Ven was only suffering from tightness against Chelsea and not a recurrence of his previous thigh problem.
The Lilywhites lost Ben Davies to a serious hamstring injury against Bournemouth last week, while Guglielmo Vicario, Richarlison, Wilson Odobert and Mikey Moore are also unavailable alongside the suspended Rodrigo Bentancur.
Which Tottenham games could Romero miss?
Romero's injury coincides with the unrelenting festive period, during which Tottenham will be competing in no fewer than four competitions in the shape of the Premier League, Europa League, EFL Cup and FA Cup between now and the middle of January.
Should Romero take the full six weeks to make his recovery, the centre-back could miss as many as 10 matches between now and the middle of January, most likely including the North London derby against Arsenal on January 15.
Romero will also be unavailable for the EFL Cup quarter-final with Manchester United on December 19, as well as the visits of Liverpool and Newcastle United to North London on December 22 and January 4 respectively.
Postecoglou should also have to make do without Romero for the FA Cup trip to Tamworth next month, although he would have likely been rested for that game anyway, while Nottingham Forest (Boxing Day) and Wolverhampton Wanderers (December 29) will come too soon as well.
There is a chance that the 26-year-old could be back in time for the Premier League trip to Everton on January 19, which would be exactly six weeks since his injury, or the Europa League battle with Hoffenheim on January 23.
More immediately, Spurs must work around his absence for Thursday's Europa League scrap with Rangers, before they return to Premier League action away to Southampton on Sunday.
Written by
Ben Knapton