With Louis Saha and Paul Scholes on the substitute's bench, and Ryan Giggs and Nemanja Vidic injured, the United boss brought in Kieran Richardson, Mikael Silvestre, Darren Fletcher and John O'Shea.
Cristiano Ronaldo was switched from his normal wide berth to a more central striking role alongside Wayne Rooney.
But, unlike the Champions League game in Copenhagen when a United side containing several shadow players was surprisingly beaten 1-0, this time Ferguson's side had too much in reserve for Everton.
The Merseysiders had drawn on their last two visits to Old Trafford and they frustrated United until six minutes before half-time. Then, Richardson found Ronaldo hovering just outside the Everton box.
His path sideways to his right found Michael Carrick and, although the England man's shot from 25 yards was blocked, the rebound fell to Ronaldo who scored with a low left-foot shot from just outside the penalty area.
Everton had to come out of their shell at the start of the second half if they were to get back into the game, but the contest was effectively over after 63 minutes.
O'Shea found Rooney just outside the Everton box on the left and he played the ball to overlapping full-back Patrice Evra running into the box.
Evra took the ball in his stride before drilling a low left-foot shot beyond Everton goalkeeper Richard Wright and into the far corner of the net for his first goal since joining United from Monaco at the start of the year.
It was a pivotal moment for Rooney as the former Everton favourite, who was vilified mercilessly by the Goodison fans, had seconds earlier turned to them and kissed the badge on his United shirt.
Rooney also played his part in United's third goal a minute from time. His 25-yard shot was blocked in the box. The rebound fell to Evra on the left by-line and his pass back into the centre was nonchalantly flicked home by O'Shea, right-footed from six yards on the near post.
Everton had competed well with United in the opening half-hour. Leon Osman tested Edwin Van der Sar with a 20-yard shot which the United goalkeeper saved diving across his goal.
James McFadden drove a shot wide soon after, after capitalising on Carrick's indecision 30 yards from goal.
But United looked the more menacing. They were lucky to win a 23rd minute free-kick when Phil Neville was penalised for handball after the ball had touched his chest.
Richardson almost capitalised on the situation when his raking free-kick from the left corner of the box clipped the bar on its way over.
Rooney's glancing header from a Silvestre cross flashed narrowly wide soon after and Gary Neville headed straight at Wright when he ghosted in on the blind side of the defence to meet Rooney's deep cross from the left.
Wright did well to turn behind Rooney's low 20-yard drive just before the break and Everton's gradual fade-out became more apparent after the interval.
Their only second-half chance came when Joseph Yobo headed a Mikel Arteta corner narrowly over the bar five minutes from time.