Within the opening 10 minutes of their 3-2 Premier League win over Newcastle United, Ederson was clattered into by Sean Longstaff, and despite trying to soldier on, he was eventually replaced by Stefan Ortega.
Guardiola did not speculate on the severity of Ederson's injury after the game, and fans will seemingly be left in the dark until the Catalan coach sheds some more light on the issue in his pre-game press conference.
When Guardiola faces the media, he should also offer an answer on whether John Stones (ankle) or Manuel Akanji (knock) will be fit for the contest, but Erling Haaland has suffered a setback in his recovery from a foot issue and is not expected to make the cut.
With Ederson's availability currently up in the air, Ortega should prepare to start in between the sticks at the Tottenham Hotspur Stadium, where Kyle Walker, Ruben Dias, Nathan Ake and Josko Gvardiol are likely to form an unaltered defence.
As Kalvin Phillips edges closer to a loan move to West Ham United, Rodri and Mateo Kovacic ought to reprise their midfield roles, but there is scope for an alteration further up the field.
In his first top-flight appearance since August, Kevin De Bruyne inspired Man City to their remarkable fightback success at St James' Park, and the Belgian will surely now be considered for a long-awaited recall to the first XI.
Jeremy Doku may be the unfortunate soul to lose his place to De Bruyne, as Guardiola deploys Bernardo Silva, Julian Alvarez and Phil Foden - who has had a direct hand in 16 goals from 14 FA Cup starts - in the final third.
Manchester City possible starting lineup:
Ortega; Walker, Dias, Ake, Gvardiol; Rodri, Kovacic; Silva, De Bruyne, Foden; Alvarez