Mohamed Salah scored twice as the champions-elect equalled a Premier League record with a 20th straight home win at Anfield.
Southampton believed they should have had a penalty early in the second half when Danny Ings went down in the box against his old club, but no spot-kick was given. Liverpool went straight up the other end to take the lead through Alex Oxlade-Chamberlain.
“The game would have been going in a different direction,” admitted Liverpool boss Jurgen Klopp.
“We had to change in the second half. That helped massively and when we are rolling it’s difficult to stop.”
Jordan Henderson doubled the European champions’ lead with a smart finish on the hour mark.
Salah then produced two cool finishes in the final 20 minutes as Klopp’s men took their tally of points to a remarkable 100 from the last possible 102.
Having completed his move from Sporting Lisbon on Thursday, in a deal worth an initial £47 million ($61.2 million), Fernandes went straight into the starting line-up at Old Trafford.
The 25-year-old midfielder delivered a composed display full of neat passing as he lined up behind United striker Anthony Martial and took the role of chief creator.
He kept Rui Patricio on his toes with a series of long-range drives, one of which the Wolves goalkeeper nearly spilled into his own net.
There was also a booking for Fernandes for pulling back Raul Jimenez in the second half of a tame clash that left sixth-placed United without a win in their last three league games.
“Bruno is a top player. It’s the first game. Bruno is one of those who, when he gets it into feet, he wants players moving in front of him and we didn’t,” United manager Ole Gunnar Solskjaer said.
“We’ve played so many games in the past few months the players are down to the bare bones. Energy levels are down and we need a break.”
Leicester and Chelsea consolidated their places in the top four in a 2-2 draw at the King Power Stadium.
Fourth-placed Chelsea sit five points clear of fifth-placed Sheffield United and six ahead of United and Wolves.
Frank Lampard’s men have won just four of their last 13 league games and needed two goals from centre-back Antonio Rudiger just to claim a point.
“Not many people gave us the top-four slot and I understand why, and it’s probably the same now,” Lampard said.
Blades on the rise
All the goals came in the second half as Rudiger nodded Chelsea in front before two goals in 10 minutes from Harvey Barnes and Ben Chilwell turned the game around for Leicester.
A brilliant leap from Rudiger 19 minutes from time denied the Foxes all three points, but Brendan Rodgers’ men maintain an eight-point lead over Chelsea in third.
Sheffield United are Chelsea’s closest challengers as Chris Wilder’s men earned a 1-0 win at Crystal Palace thanks to a calamitous own goal from Eagles goalkeeper Vicente Guaita.
A double for Robert Snodgrass after Issa Diop’s opener put West Ham 3-1 up against Brighton at the London Stadium, but the Seagulls fought back through Pascal Gross and Glenn Murray for a point that keeps them two points above the drop zone.
Watford failed to even collect a point after going 2-0 up on Everton through Adam Masina and Roberto Pereyra.
The Hornets switched off from two set-pieces in first half stoppage time to allow Yerry Mina’s double to bring Carlo Ancelotti’s men level.
Everton then went down to 10 men when Fabian Delph was sent off but snatched all three points through Theo Walcott.
Aston Villa’s celebrations at reaching the League Cup final in midweek were short-lived as 10-man Bournemouth held on for a 2-1 win that lifted them up to 16th.
Norwich are seven points adrift of safety at the bottom of the table after a 0-0 draw at Newcastle.
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