Ferdinand picked up a calf injury during the warm-up for last weekend's match against Wolverhampton Wanderers, where leaders United suffered their first league defeat of the season.
"He (Ferdinand) will be out for a couple of weeks, Jonny Evans got injured training with (Northern) Ireland so he's out, so young Chris Smalling will play tomorrow," Ferguson told a news conference.
The 21-year-old Smalling, who joined United from Fulham last year, is likely to partner captain Nemanja Vidic in the centre of defence for the match at Old Trafford.
Ferguson was counting on United's home form - where they have dropped just two points this season - to help them to a win that would open up a seven-point lead for a few hours at least and damage City hopes of a first league title since 1968.
"Tomorrow could be a decisive game in terms of the championship for both teams and it makes it an interesting game for us," Ferguson said.
"Hopefully our home form stacks up because it's been excellent this season... you never get easy games in derby games but I'm going into the game with good confidence in the sense of our home form."
This fixture last season was a thriller described by Ferguson then as "probably the best derby game of all time" after his team won 4-3 thanks to a Michael Owen goal in the sixth minute of stoppage time in a match where City came from behind to level three times.
This season's derby at Eastlands failed to live up to expectations when the two sides played out a scrappy 0-0 draw where neither looked like worthy title contenders.
United avoided paying a higher price for last weekend's 2-1 defeat at relegation-threatened Wolves thanks to Arsenal drawing and Chelsea losing.
"You do lose games in this Premier League and in the run-in to the end of the season teams will drop points... whoever gets the most consistent form will win the league," said Ferguson.
With 54 points, Ferguson's side are four points clear of second-placed Arsenal and five above third-placed City who have played a game more. Champions Chelsea trail the leaders by 10 points in fourth.
