The Spain international was forced off after just 23 minutes of Sunday's FA Cup semi-final loss to Arsenal with a hamstring injury, having been hit hard by tackle from Gabriel moments earlier.
Striker Sergio Aguero has a better chance of featuring despite suffering a knock in the same game, while only match-fitness is now holding fellow forward Gabriel Jesus back.
Jesus, who scored three goals in four starts after joining the club in January, has been out since breaking a bone in his foot in February.
Guardiola said: "David Silva is a real, real doubt, I don't know if he will be ready to play after what happened in the first minutes in the semi-final of the FA Cup.
"Gabriel has no pain at all, so is ready but has had three months out, so his physical condition is not optimal.
"Sergio is much better. Today he makes a short part of the training session, tomorrow we will wait (and see)."
The stakes are high in the third Manchester derby meeting of the season, with Champions League qualification points on the line.
City, fourth in the Premier League, are just a point ahead of their arch-rivals, who have not lost in the competition since October, in a tight battle.
Guardiola said: "They are good, good rivals, good quality, in good form. They've had big series without defeat in the Premier League. They have a lot of quality, history. We're looking forward to the game."
The September derby at Old Trafford was hyped to an extraordinary level for a regular league fixture, with a lot of the attention focusing on the managers.
Read the full article on eurosport.co.uk: Guardiola says Silva is a major doubt for Manchester derby