Substitute Nani made an immediate impact soon after coming on in the fifth-round tie at Old Trafford on Monday night, breaking the deadlock with a right-foot drive which flicked off Sean Morrison and past Adam Federici after 69 minutes.
The hosts doubled their advantage three minutes later as Javier Hernandez met the Portuguese winger's cross at the near post to head in his 15th strike of the campaign.
Reading pulled a goal back with time running out after some woeful defending allowed Jobi McAnuff time to slot his effort away.
The Red Devils could have added a third late on as the Royals pushed on, but it was United who progressed in the end.
However, an injury to Phil Jones took the gloss off a victory that keeps United on track for a repeat of their historic 1999 treble, and Sir Alex Ferguson on course for a possible encounter with Rafael Benitez, whose Chelsea team must beat Middlesbrough for the right to face the Old Trafford giants in the last eight.
Reading goalkeeper Federici was forced to deny Danny Welbeck and Ashley Young had a shot blocked before the visitors soon got into their stride, with Noel Hunt to the fore.
Hunt sustained a nasty cut following a collision with Nemanja Vidic that required two shirt changes, but also set the pattern for a bruising collision between the pair.
The sharpness had soon gone out of United's play, although they should still have been in front after Federici pushed Tom Cleverley's long-range effort into Ashley Young's path. It seemed the England man only had to hit the target. But Federici was able to scramble across to push the shot wide when really he should not have had chance to.
Funnily enough, Jones' departure, while potentially a major blow to Ferguson's plans for subduing Ronaldo next month, sparked the hosts into life. Nani's third touch following his introduction as Jones's replacement saw him strike the far post with a fine volley, while his fourth was tipped over by Federici's flying save.
There was one more save from Federici before the dam finally broke. Nani's introduction had undoubtedly been significant and moments after his effort had been repelled, he strode onto Valencia's cross and supplied a deadly finish.
When Hernandez flashed home a near-post header on United's next attack, it appeared their work was complete.
Instead, McAnuff struck nine minutes from time to bring a familiar sense of nervousness to Old Trafford which only Andre Marriner's final whistle was able to ease.
|Manchester United||Team Statistics||Reading|
|0||1st Half Goals||0|
|10||Shots on Target||3|
|9||Shots off Target||4|
|62.5||1st Half Poss.||37.5|
|60.4||2nd Half Poss.||39.6|