None of the players who started in the 1-1 Premier League draw at Chelsea on Sunday featured, but Cristiano Ronaldo began a match for the first time this season.
It was the 23-year-old Portugal star, now fully recovered from his ankle operation, who opened the scoring for the Red Devils in the 25th minute.
Although Boro sub Adam Johnson equalised nine minutes after the interval, late goals by Ryan Giggs and Nani gave United a deserved victory.
The only worry for United was the 66th minute injury suffered by midfielder Rodrigo Possebon.
The young Brazilian was sent crashing to the ground by a horrific tackle from Boro skipper Emanuel Pogatetz.
Referee Andre Mariner had no option but to dismiss Pogatetz, while United's medical staff attended to Possebon for a large gash on his right leg and it was six minutes before play resumed.
United went at Boro from the start, but it took them 25 minutes to break the deadlock.
Giggs curled a corner into the centre of the Boro box and Ronaldo rose above Mohamed Shawky and Didier Digard to head home from eight yards.
United should have doubled their lead three minutes later when Boro goalkeeper Brad Jones saved well from a close range shot by 19-year-old debutant striker Danny Welbeck.
Jones denied Ronaldo a second goal three minutes before the break when he put behind the United star's shot from the edge of the box with his legs.
Jones produced another brilliant save to deny Welbeck early in the second half and it was Boro who equalised in the 56th minute.
Gary O'Neil's cross from the right side of the penalty area looked to have been cleared by Nemanja Vidic's powerful defensive header, only for the ball to fall nicely for Johnson who scored with a crisp right-foot shot from 25 yards.
United regained the lead with a glorious goal from Giggs after 74 minutes.
Boro substitute Chris Riggott slipped as he tried to cut out a long ball from United substitute Darron Gibson.
Giggs raced through to score with a superb left-foot chip over Jones and into the net from 12 yards.
United could have had more goals, but they had to wait until five minutes into injury time for their third.
Another Boro defensive error - this time by David Wheater - was punished by Nani when he pounced to score with a right-foot shot ten yards out.