A red card for Saints’ Alexandre Jankewitz after only two minutes triggered a complete collapse for the visitors, who were on the end of the same scoreline against Leicester City in October 2019.
It is only the third time a team has lost 9-0 in the Premier League, with United also beating Ipswich Town by that margin in 1995.
Aaron Wan-Bissaka opened the scoring with his first goal at Old Trafford. Marcus Rashford and Edinson Cavani also found the net either side of a Jan Bednarek own goal before the break.
After a fairly drab start to the second half, United cut loose, scoring five times in the final 21 minutes.
Anthony Martial ended an eight-match goal drought before Scott McTominay drove home from the edge of the area.
Then, after Bednarek became the second Saints player to be sent off – bringing down Martial to allow Bruno Fernandes the chance to score from the penalty spot – the French forward netted his second, before Dan James wrapped up the scoring in stoppage time.
It was a stunning ending as United almost matched their club record 10-0 victory against Anderlecht in 1956.