The 23-year-old picked up the issue after playing 74 minutes at Old Trafford as Spurs rescued a 1-1 draw away to Manchester United.
Speaking to Sky Sports before kick-off, De Zerbi said: "Destiny Udogie played 70 minutes, and he suffered a problem in his knee, and we didn't take a risk."
Udogie had featured in four of Tottenham’s six Premier League matches thus far but now seems to be facing a spell on the sidelines.
Injury blow: Destiny Udogie
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De Zerbi has rung the changes against Coventry, handing James Maddison his first competitive start since April 2025, while Tosin Adarabioyo makes his full Premier League debut.
There is also a start in midfield for Archie Gray, who has been filling in at right-back this season, with Tosin at right-back and youngsters Luca Williams-Barnett and Callum Olusesi on the bench.
Dejan Kulusevski is also among the substitutes, having spent more than 500 days on the sidelines with a complicated patella injury, which has required two separate surgeries.
This is the latest injury setback for Udogie, who has struggled with a succession of knee and muscle injuries since signing from Udinese in 2023.
He joins Savio, Pedro Porro, Mykhailo Mudryk, Xavi Simons, and Wilson Odobert on the treatment table, while the suspended Rodrigo Bentancur, who was sent off for a headbutt on United defender Luke Shaw, is also absent.