His injury comes as another massive blow for De Zerbi in his attempts to keep Spurs in the Premier League.
With four games to go, Spurs are two points from safety after West Ham secured a stoppage-time victory at home to Everton.
Here, Standard Sport looked at three ways Spurs could line up without Simons…
Mathys Tel
Getty
Tel finally gets his chance
Mathys Tel has continued to find himself out of favour since De Zerbi took over from former interim manager Igor Tudor.
The 21-year-old has yet to start under the Italian after also struggling for minutes under Tudor and Thomas Frank.
But with Simons out for the remainder of the season, the Frenchman could be given the opportunity to impress after a series of productive cameos off the bench.
It was Tel’s intensity that forced the corner from which Joao Palhinha scored against Wolves, and his directness adds a different dimension for Spurs.
De Zerbi remains a fan of Tel, having tried to sign him when he was Marseille manager, and hinted that he could be given more minutes as he looks for answers to Simons’ injury.
Tottenham XI (4-2-3-1): Vicario; Porro, Danso, Van de Ven, Spence; Bissouma, Bentancur; Kolo Muani, Gallagher, Tel; Richarlison
Lucas Bergvall has only recently returned from injury
PA
Bergvall comes back into the side
In De Zerbi’s first game in charge, a 1-0 defeat to Sunderland, he opted to play Lucas Bergvall in the No10 role with Richarlison out wide on the left.
It was a decision that did not pay off, as Spurs lacked any authority in the centre of the park and struggled to create chances in the final third.
Now, though, with Simons out, De Zerbi may be minded to go give the young Swede another chance, having insisted he is not keen to make drastic selection decisions between now and the end of the season.
While Bergvall often struggles to dictate play, he remains an excellent presser of the ball, as he showed in turning over possession for Simons’ goal against Brighton.
De Zerbi could feasibly bring both Bergvall and Tel into his starting line-up, with Richarlison potentially spearheading the attack in place of Dominic Solanke, who came off injured against Wolves.
Tottenham XI (4-2-3-1): Vicario; Porro, Danso, Van de Ven, Spence; Bissouma, Bentancur; Kolo Muani, Bergvall, Tel; Richarlison
James Maddison has made the bench in the last two games
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De Zerbi takes a risk on Maddison
The Englishman, who suffered an ACL injury last August, has been named on the bench in each of Spurs’ last two games, but has yet to play a single minute.
With games running out for Spurs to save themselves, though, De Zerbi could take a risk by handing Maddison his first minutes in more than eight months.
Maddison is a potentially game-changing talent when fit. But as De Zerbi found out when Mohammed Kudus suffered a setback in his recovery from a serious quad injury, he has to be careful not to force players back.
Capable of playing off the left and drifting centrally or starting from the No10 position, Maddison is a versatile option who would solve Spurs’ creative issues.
The question is whether De Zerbi feels he is ready to come into a relegation battle.
Tottenham XI (4-2-3-1): Vicario; Porro, Danso, Van de Ven, Spence; Bissouma, Bentancur; Kolo Muani, Gallagher, Maddison; Richarlison
