The visitors, who had beaten Milton Keynes 3-1 in their opening game, did the damage in a seven-minute spell towards the end of the first half when they scored two goals from corners.
Argyle had some chances and should have scored at least one goal, but Southampton just had that bit extra on the day.
The Pilgrims, who had lost away to Portsmouth in their season-opener the previous week, started quite well on Sunday, but then the Saints started to get control of the ball.
There was not too much to get excited about in the opening half-an-hour, but on 32 minutes Southampton broke the deadlock with a well-worked corner. They delayed their cross into the box but when it did come in, defender Leeta Rutherford timed her jump perfectly to produce a powerful header that Argyle goalkeeper Poppy Soper had no chance of saving.
Argyle should have reduced the deficit on the stroke of half-time. From a corner the Southampton keeper came out but failed to gather and the ball fell perfectly for Natasha Knapman at the back post but her header just went wide.
The Pilgrims had another great chance at the start of the second period from another corner but then Southampton settled again.
The visitors had a goal disallowed on 60 minutes before appealing for a penalty four minutes later when Argyle’s Tracey Cross tangled with Saints substitute Georgie Freeland. The referee, though, ruled the foul had happened just outside the box.
Soper made a great save from close range on 75 minutes but she could not prevent Southampton making it three a minute later when Ciara Watling had a tap-in at the far post after a great run and cross by Freeland.
Argyle kept battling and had a couple of late chances but the Saints keeper was there to deny Knapman and Beth Ireland.
Signal Box played two back-to-back matches against Liverton United and Ilfracombe Town.
They lost 6-2 to a physical Liverton side, with Abi White and Katelyn Berry scoring their goals, before they beat Ilfracombe Town 3-1 with captain Vicky Jasper bagging a hat-trick.
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