The 25-year-old started the match for the Saints at St Mary's Stadium, where the hosts had the better of the first-half possession and chances.
A turning point of the contest arrived during the opening 45 minutes, when summer arrival Cameron Archer saw his penalty attempt saved by Red Devils goalkeeper Andre Onana.
Before the half-time whistle, Man United clicked into gear and fired themselves into a two-goal lead courtesy of efforts from Matthijs de Ligt and Marcus Rashford.
Erik ten Hag's troops assumed control of the match in the second period and added a third late on, with Alejandro Garnacho beating Aaron Ramsdale in the Saints net.
Southampton's Brereton Diaz breaks unwanted Premier League record
At the 64th-minute mark on Saturday afternoon, Ben Brereton left the field of play to make room for Ryan Fraser, with the summer arrival failing to find the net so far this season.
With the full-time whistle sounding with the scoreline at 3-0, the Chilean broke a Premier League record for the most appearances in the league without victory.
The 25-year-old has now played 18 games in England's top flight across spells at Sheffield United and Southampton without being part of a winning side.
Adding to Brereton Diaz's pain, he has now suffered 11 straight Premier League defeats stretching back to the middle of April, when he was plying his trade at Bramall Lane.
The former Man United youngster will be looking to enjoy a maiden victory on his 19th top-flight appearance when the Saints host fellow newly-promoted side Ipswich Town at St Mary's on Saturday.
Brereton Diaz is not to blame
Enduring 18 Premier League matches without tasting success, it would be easy to assume that Brereton Diaz has performed poorly so far in his top-flight career.
The 25-year-old has not been helped by the states of his employers during that period, Sheffield United were the whipping boys of the division last campaign and Southampton have failed to collect a point so far this term.
Brereton Diaz has netted six goals across those 18 Premier League appearances, a highly-respectable return considering the strength of his teammates.