Captain fantastic Keane struck the decisive blow early in the second half as he ended his 15-month wait to reach his half-century.
Until Keane found the net it looked as though it would be a frustrating afternoon for United as old boy Steve Bruce's Blues threatened to grind out a draw.
United, for the best part of an hour, must have feared a reaction after their emotionally charged win at Arsenal in midweek.
Once Keane opened his account, United settled and sealed victory late on with a goal from Wayne Rooney, his 12th of the season.
It extended United's unbeaten record in the Premiership to 15 matches and they have taken 39 points from a possible 45 to remain the closest challengers to leaders Chelsea.
And though it was by no means a vintage display, United's win was equally as important as their success at Highbury four days earlier.
Sir Alex Ferguson saluted Keane, not only for his 50th goal but also his terrific performance.
He said: "He revisited old times and that was the Roy Keane of ten years ago.
"In 30 years time, or if this club is still going in 500 years, he will still be one of its greatest ever players."
Ferguson was pleased with his side's performance adding: "It was a good result bearing in mind the emotion and task we faced on Tuesday, and the pitch was also not that great.
"We were too pedantic in the first half and the pace was far too slow.
"But we've showed more urgency in the second period and, when we needed something to open up Birmingham, Roy provided that."
Blues manager Bruce, a former team-mate of Keane's, also paid his own tribute.
He said: "He is a top player and proper captain who leads by example and he will be a hard act to follow.
"When United needed a piece of inspiration after an hour, Roy gave it to them. He is a huge player as we also saw in the win at Highbury."
Bruce added that his side faced an even tougher challenge at Old Trafford bearing in mind their squad was ravaged by injury.
"Walter Pandiani was two inches away from a goal and Julian Gray had an incredible chance just after half time and you have to take chances like those when you come to Old Trafford," he explained.
Both teams made two changes following their midweek victories.
United handed starting spots to John O'Shea and Louis Saha who replaced the injured Darren Fletcher and Paul Scholes who was rested after the victory at Arsenal.
Martin Taylor was recalled to the centre of the Blues defence as Matthew Upson was ruled out with a hamstring injury.
New Tunisian signing Medhi Nafti - who was captured on the final day of January's transfer window - was drafted into midfield in place of Steven Clemence whose partner is expecting the birth of their baby.
Blues keeper Maik Taylor was called into action for the first time in the eighth minute with an agile tip over to divert Cristiano Ronaldo's free-kick over the crossbar.
Pandiani, signed on loan from Spanish side Deportivo La Coruna, had the Blues' first strike at goal but his 25-yard drive flew narrowly wide.
The nearest to a goal came midway through the half when Rooney's header from Rio Ferdinand's cross was pushed against the upright by Taylor diving low to his left.
United went close again when Ryan Giggs was put through by Ronaldo's inch-perfect pass only to roll his effort narrowly wide.
United then had a lucky escape following a poor headed clearance by Ferdinand. Pandiani struck a venomous volley from the right side of the penalty area which struck the crossbar and bounced down onto the goal-line, but luckily for United stayed out.
Blues' Damien Johnson became the first player to be booked in first-half stoppage time following a cynical trip on Giggs whose burst of pace had left him for dead.
United were denied by the woodwork for a second time when Ronaldo's deep cross from the right floated over Taylor's head, but struck the upright and bounced to safety.
United eventually broke the deadlock in the 55th minute from an unlikely source as Keane ended his lengthy goal drought.
Ronaldo's clever back-heel released Keane who burst into the penalty area following a surging run and he drilled home an unstoppable shot low to the right of Taylor.
Ferguson made a switch midway through the second period taking off Saha and replacing him with Quinton Fortune. This left Rooney as the lone front-runner with Giggs and Ronaldo pushing forward from the wide positions.
This was quickly followed by two changes by the Blues as Robbie Blake and Nafti were taken off and replaced by Clinton Morrison and Darren Carter.
Rooney went close again when a ferocious shot from the right side of the penalty area flew inches over the crossbar. And not long after Taylor had to make a diving save to deny Giggs.
Rather like waiting for a bus, Keane so nearly scored his second goal of the match when he burst through the Blues defence once again only this time to be denied by a smart save from Taylor diving low to his left.
United sealed victory in the 78th minute after a piece of calamitous defending from the visitors
Kenny Cunningham put Taylor in trouble with a dreadful back-pass which the keeper did well to block as Ronaldo burst through on goal.
Unfortunately for the keeper, the rebound fell to Rooney who found the net with an exquisite chip.
The goal was immediately followed by Rooney and Giggs being substituted by Phil Neville and Liam Miller as Ronaldo ploughed a loan furrow up front.
MAN OF THE MATCH: Roy Keane (Manchester United) - Produced a display reminiscent of his hey-day and capped it by scoring his 50th goal for the club.