Second-half goals from Nani and Javier Hernandez earned United a place in the sixth round of the Cup on a night of fierce Royals resistance at Old Trafford.
The hosts toiled in a bid to carve Reading open, only to find goalkeeper Adam Federici in inspired form either side of the interval.
United were much-changed with Sir Alex Ferguson opting to leave Robin van Persie on the bench and exclude Wayne Rooney entirely.
But the visitors still had to weather an early storm, with Federici called upon to deny Tom Cleverley and then Nani, a first-half substitute for Phil Jones, who also hit the post.
Manager Ferguson summoned top scorer Van Persie from the bench in a bid to avoid the need for a replay. But it was Nani who broke Royals hearts with 21 minutes remaining, firing home a deflected effort before crossing for Hernandez to seemingly kill the game off three minutes later.
However, Jobi McAnuff’s neat finish with nine minutes left ensured Reading, for whom Noel Hunt suffered a nasty head injury, had hopes of a late leveller.
But United stood firm through five minutes of injury time and go through to face Middlesbrough or holders Chelsea in the last eight.
Manchester United’s Tom Cleverley (R) challenges Reading’s Jem Karacan (Reuters)
On his way: Antonio Valencia is heading for the United exit door (Picture: AFP/Getty)
Manchester United’s Javier Hernandez (L) in action against Reading’s Sean Morrison (2-L), Stephen Kelly (2-R) and Adam Federici (R) (EPA)
Reading’s manager Brian McDermott reacts (EPA)
Manchester United’s Ashley Young right, and Reading’s Garath McCleary left, battle for the ball (AP)
Danny Welbeck of Manchester United is tackled by Nicky Shorey of Reading (Getty)
Reading’s Nicky Shorey (right) and Manchester United’s Antonio Valencia (left) battle for the ball (PA)
Manchester United’s Javier Hernandez bottom, and Reading’s Jem Karacan, top, battle for the ball (AP)
Nani of Manchester United holds off a challenge from Adam Le Fondre of Reading (Getty)
Manchester United’s Tom Cleverley (R) challenges Reading’s Jem Karacan (Reuters)
Manchester United’s Alexander Buttner (L) challenges Reading’s Garath McCleary (Reuters)
Manchester United’s Chris Smalling, top, and Reading’s Adam Le Fondre contest a header (AP)
Real doubt: Phil Jones could be struggling to race Madrid (Picture: Getty)
Manchester United manager Sir Alex Ferguson gestures towards the fans (PA)
Manchester United’s Luis Nani celebrates scoring his side’s first goal of the match
Manchester United’s Mexican striker Javier Hernandez (R) celebrates scoring his team’s second goal with Manchester United’s Brazilian midfielder Anderson (AFP/Getty)
Reading’s Danny Guthrie (L) in action against Manchester United’s Anderson (EPA)
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