The Red Devils recorded their seventh straight victory in league and cup competitions as they built on their recent good form.
Now unbeaten in nine matches, United overcame a stubborn Saints side after a dazzling second-half display and in the end they could have won by much wider margin.
United's revival has coincided with Paul Scholes' return to form.
After going seven months without a goal, the former England player scored his fourth in as many matches to break the deadlock early in the second half.
That was quickly followed by Wayne Rooney's seventh of the season and Cristiano Ronaldo capped a fabulous second-half performance by scoring United's third in the dying minutes.
United, whose first-half display was lukewarm, certainly have no difficulty scoring against the Saints as they have now found the net 31 times in the last 11 meetings.
Sir Alex Ferguson was delighted by his side's showing, saying: "Some of the football we played in the second half was exceptional and we could have scored even more goals.
"Teams like Southampton are fighting for every point and that makes it difficult.
"You have to be patient and not frustrated then open them up gradually."
Ferguson added that his side now has the bit firmly back between their teeth.
He enthused: "You can smell it about the place. The confidence is back, we are looking forward to games and our training sessions have also been good."
And in the race for the Premiership title, United consolidated their hold of fourth place with Ferguson saying: "We are nine points behind Chelsea which will be a mammoth task to claw back.
"But there is a long way to go and maybe it will have changed by New Year's Day?"
That is the date Ferguson uses as a barometer to gauge his side's prospects in the Premiership.
Southampton head coach Steve Wigley was disappointed by his side's second half showing, explaining: "We probably came here at the wrong time on the back of seven straight victories for United.
"We knew it would be difficult but felt if we applied ourselves like we did against Arsenal we might have got something.
"We did our job in the first half, but gave away a poor goal earlier in the second when we had one or two opportunities to clear.
"There was a lack of concentration and after the goal the belief drained out of the players."
Alan Smith partnered Rooney upfront after Ruud van Nistelrooy was ruled out with a calf strain.
And Gary Neville returned at right back after recovering from a virus as Wes Brown stood down.
Saints had striker James Beattie back after injury to partner Kevin Phillips as Wigley was able to field his first choice strike pairing.
It was evident from the kick off what sort of match it would it be with United attacking and Saints forced to defend and rely on counter attacks.
And in a one-sided opening Ryan Giggs, Rio Ferdinand and Neville all had attempts on goal in the first six minutes.
Ronaldo then made a dangerous run down the right and squared the ball for Scholes who dragged his shot wide.
Saints had to wait 20 minutes before creating their first clear-cut chance when Phillips' drive flashed wide of the upright.
The visitors was dealt a body blow midway through the opening period when Beattie limped off with a recurrence of a calf strain and was replaced by Dexter Blackstock.
After a bright and lively opening the match lost it sparkle and became bogged down in a dour midfield battled.
Indeed, United went 28 minutes without creating an opening and amazingly had three scoring opportunities in quick succession.
Gabriel Heinze hit a shot straight at Kasey Keller and then Rooney headed wide when it looked as though he could not miss.
Giggs had United's best opening in the 35th minute when he ran on to Scholes' pass and unleashed a furious long-range drive which whistled just wide of the post.
Keller, Saints' on loan goalkeeper, pulled off excellent saves to deny Ronaldo and Rooney as United finished an opening half in complete control.
The second half began in a similar fashion with Ronaldo and Rooney squandering excellent chances before the Reds finally made the breakthrough in the 53rd minute.
Saints failed to clear the danger and Ferdinand volleyed a sideways pass for Scholes to head home from inside the six-yard box.
Ronaldo came close to doubling their lead soon after with a low shot which flew inches wide.
But a second goal arrived in the 58th minute following a glorious three-man move involving Heinze, Giggs and Rooney who smashed an unstoppable shot into the roof of the net.
The floodgates looked as though they were about to open as Ronaldo's free-kick was brilliantly saved by Keller and Scholes came within a inch of scoring when his lob was acrobatically tipped over the crossbar.
There was no respite for Saints as substitute David Bellion set up Ronaldo whose far post shot struck a post.
Keller then produced another great save to deny Scholes with Ronaldo firing the rebound over the bar when he looked certain to score.
But Ronaldo found the net for the first time this season in the 87th minute with a move which he both started and finished.
The Portugal international fired the ball across the face of goal before latching on to Neville's lay-off and smashing home a low shot.
MAN OF THE MATCH: Cristiano Ronaldo (Manchester United) Another dazzling display by the winger which was capped by his first goal of the season.