Smalling will be charge with keeping former United star and City captain Carlos Tevez under close consideration in a crucial match for Sir Alex Ferguson's title chasing side, who are looking to bounce back from last weekend's first defeat of the season at Wolves.
Striker Javier Hernandez is also missing for the hosts after international duty with Mexico in mid-week.
Big test: Smalling will step in for injured Ferdinand in the crucial Manchester derby at Old Trafford
Ferdinand has not recovered from the calf injury he sustained in the warm-up ahead of Manchester United's shock defeat at Wolves last week.
Evans played in that game but missed Northern Ireland's hammering by Scotland on Wednesday with an ankle injury and is still sidelined.
Missing men: Ferdinand and Evans are both out of the crunch Manchester derby due to injury
'Rio Ferdinand got a calf injury last week. He will be out for a couple of weeks,' confirmed Ferguson.
'Jonny Evans was injured in training with Northern Ireland. He is out so Chris Smalling will play. I am sure he will do well.'
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