With 76 places separating the two teams in the Football League pyramid, Manchester United were widely expected to progress with ease in to the fifth round.
However, League Two side Cambridge - promoted from the Conference last season - put in a solid showing in front of their own supporters and were rewarded with another shot at Louis van Gaal's men at Old Trafford.
Indeed, it was Cambridge who fashioned the best chance of the first half when Josh Coulson nodded over the crossbar from close range.
The visitors were frustrated throughout the opening 45 minutes as Radamel Falcao forced Cambridge goalkeeper Chris Dunn into a fine save just after the hour mark, while substitute Robin van Persie also went close.
However, the wealth of attacking talent at Manchester United's disposal were unable to find the breakthrough against Richard Money's men in a below-par showing.
Falcao and James Wilson started up front for the visitors in the absence of the rested Wayne Rooney, while Adnan Januzaj was handed his first start since November.
The hosts had captain Tom Champion available after a knee injury scare, while former Manchester United midfielder Luke Chadwick was on the bench.
Marouane Fellaini's foul on Norwich City loanee Cameron McGeehan handed Ryan Donaldson the chance to deliver a teasing free-kick that Tom Elliott headed just wide after eight minutes.
The visitors posed their first threat two minutes later when Daley Blind scampered down the left before forcing a near-post save from Dunn, but they were let off at the other end when Liam Hughes side-footed wide from Donaldson's poorly defended corner.
A wayward pass from Phil Jones almost handed the lively Donaldson, scorer of the winning goal in the last round against Luton Town, an opportunity, but the former Newcastle United midfielder's first touch let him down and the danger was snuffed out.
With Van Gaal's side struggling for fluency, Angel di Maria summed up their frustration by clearing the stand with a speculative effort midway through the half.
And things should have got a whole lot worse for the overwhelming favourites when Cambridge defender Coulson inadvertently cleared a goal-bound effort off David de Gea's line before heading over from point-blank range.
Di Maria still found time to swing a free-kick high and wide as the Argentina winger continued to struggle to make an impact.
The Premier League side initially struggled to lift the tempo after the break, but only a fine save from Dunn kept the scores level in the 63rd minute.
Michael Carrick's expert throughball sent Falcao free and the Colombia international fired a low shot towards goal that Dunn parried over the crossbar.
Van Gaal introduced Van Persie and the Dutchman should have scored with a close-range half-volley from a wonderful scooped pass from Di Maria.
Manchester United continued to press forward in injury time and there was late drama when Cambridge struggled to clear their lines, Dunn once more called upon to deny Di Maria's drilled effort from the edge of the penalty area.
Cambridge now add their name to the list of lower league sides that have frustrated Manchester United in the FA Cup, with Exeter City and Burton Albion having earned replays in the third round of the 2005 and 2006 competitions.
