Retribution will be firmly on United manager Sir Alex Ferguson's mind with the fierce rivals meeting almost three months after City inflicted a stunning 6-1 league defeat on their neighbours at Old Trafford.
The clash at City's Etihad Stadium is also a repeat of last season's semi-final which City won 1-0 before securing their first major trophy for 35 years by beating Stoke City in the final.
A hectic holiday programme saw both sides stutter to surprise defeats, United losing twice in five days to strugglers Blackburn Rovers at home and then at Newcastle United on Wednesday.
City were sunk by a late goal at Sunderland but their midweek 3-0 win over Liverpool helped them preserve a three-point lead at the top of the league.
City's six-goal salvo on October 23, United's worst home defeat since 1955, put them five points clear at the top and was described by Ferguson as his "worst ever day."
African Footballer of the Year and Ivory Coast international Yaya Toure will play his last game for City before leaving for the Africa Cup of Nations which gets underway later this month.
Mancini said the midfielder, who scored and set up another goal in the win over Liverpool on Tuesday, was "irreplaceable."
"I have tried to find another Yaya in my squad but there isn't another Yaya," Mancini said.
"He will be a big loss and it will be difficult because he is such an important player for us and we have so many games."
The third round draw produced just one other all-Premier League clash with Newcastle United hosting Blackburn Rovers, but there are plenty of other interesting ties.
Ten-times winners Arsenal host Championship Leeds United on Monday in a repeat of the 1972 final while Chelsea welcome Portsmouth to Stamford Bridge on Sunday in a repeat of the 2010 final which the Londoners won 1-0.
There are also some spicy local derbies in prospect, none more so than at St Andrews where Birmingham City, relegated from the Premier League last season, host Wolverhampton Wanderers.
The minnows also get their moment in the spotlight with minor league Tamworth, who play one level below the Football League, savouring a bumper payday when they take on Everton.
The magic of the FA Cup has not been lost on Tamworth who will be cheered on at Goodison Park by over 4,000 fans who will travel up from Staffordshire.
