Jan Bednarek's header and James Ward-Prowse's stunning free-kick sent Southampton in at the break with a two-goal lead, but United, who were forced into bringing Dean Henderson on at half-time in place of the injured David de Gea, hit back in
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Trent Alexander-Arnold, making a first league start in more than two months, curled a fabulous first-half free-kick into the top corner to put them ahead.
Willian opened the scoring with a well-placed free-kick after five minutes and the Brazilian added his second from the spot two minutes before the break.
The Chile international then added the second after the break, shrugging off the attentions of Masuaku to lash home a low shot before adding a third with a little over 10 minutes to go.
The hosts, however, over-ran City after the break with Willian scoring from close range and Gary Cahill putting the result beyond doubt with a powerful finish from Fernando's poor clearance.
Defender Shkodran Mustafi looped home a header from Mesut Ozil's cross, but Spurs may well feel the free-kick awarded for Davinson Sanchez's foul on Alexis Sanchez was a harsh decision.
Arsenal did have the ball in the net, Jakub Kiwior heading home after beating PSV keeper Walter Benitez to a free-kick, but it was ruled out for offside against Gabriel.