Saints ran out 5-2 victors over their Hammers counterparts on a glorious day at Staplewood in our final Elite Group fixture.
The hosts had trailed after just four minutes after Elliot Lee's well-taken opener, but Corby Moore levelled things up just before the quarter-hour.
However, the Hammers quickly restored their lead through George Moncur's penalty, only for Lloyd Isgrove to make it two-all inside first-half injury time.
Saints emerged strongly from the break, and two goals in three minutes from Sam Hoskins and substitute Omar Rowe put them well in the ascendancy.
Jake Sinclair added a fifth shortly before full time, ensuring Saints recorded the win needed to jump into the third and final play-off spot.
However, fourth-placed Liverpool still have two games to go and currently have the same number of points – so one further point will see them jump into third.
Saints, playing their second home game in the space of four days, made one change from the side that drew nil-nil with Elite Group winners Spurs on Monday, with goalkeeper Cody Cropper came back into the team in place of Paulo Gazzaniga.
The Hammers went into the match just one point better off than their hosts with two games to go, so were harbouring play-off hopes of their own.
And they made the best possible start, with forward Sean Maguire holding the ball up before cutting back for strike partner Lee to sweep beyond Cropper after just four minutes.
The Hammers could well have added a second goal three minutes later, as Maguire and Lee combined again only for the latter's header to be excellently kept out by Saints' American 'stopper.
Visiting midfielder Ben Marlow then saw an effort hurriedly cleared away from goal by Moore, before Saints winger Sinclair fired over after being picked out by Isgrove.
Saints did manage to level matter with 14 minutes gone as right-back Calum Chambers surged forward before playing a low ball across the edge of the area for Moore to sweep in only his second goal of the season.
Centre-forward Hoskins then saw a fierce effort held by West Ham goalkeeper Sam Baxter, before Jack Stephens fired a low shot wide from the best part of 30 yards out.
And it was the Saints skipper who would have a hand – literally – in the visitors' second, having been penalised by referee David Woolford to getting an arm to a cross from the right flank.
That allowed Hammers midfielder George Moncur to step up and send Cropper the wrong way to make it two-one with 29 on the clock.
With it looking like Saints would go into the break behind, they managed to claw themselves level in first-half injury time when good work on the right by Sinclair allowed him to cross for Isgrove to turn the ball beyond Baxter and inside the far post.
HALF TIME: SAINTS U21S 2-2 WEST HAM U21S
Hammers boss Nick Haycock made two changes at the break, taking off Marlow and Dan Potts to bring on Frazer Shaw and Taylor Miles.
But it was Saints who quickly moved into the ascendancy after the break, with Baxter making a good stop from Matt Targett's fierce cross before getting up to hold a Hoskins header after Sinclair had returned the ball into the box.
Either side of that flashpoint, opposing wingers Sebastien Lletget and Sinclair took turns to send drives wide of the target.
Southampton took the lead for the first time in game on 68 minutes when some determined running by Hoskins saw him nip in between Baxter and defender Callum Driver before slotting into the open goal.
Better was to follow within two minutes, when Omar Rowe – on as a 59th-minute replacement for Joe Curtis – charged down Pelly Ruddock and stole the ball before smashing past Baxter for four-two.
The hosts almost grabbed a fifth on 73 minutes when Rowe's inswinging free kick from the right almost caught out Baxter before Hoskins headed into the side-netting from an acute angle.
The final goal did eventually arrive four minutes from time, and in similar circumstance – Rowe's corner from the left found Sinclair at the back post, and he made no mistake in heading the ball home.
FULL TIME: SAINTS U21S 5-2 WEST HAM U21S
Saints U21s: Cropper, Chambers, Stephens (c), Turnbull, Targett, Curtis (Rowe 59), Reed, Moore (Gape 78), Sinclair, Hoskins, Isgrove (Seager 85). Subs (not used): Gazzaniga (GK), Young.
Goals: Moore (14), Isgrove (45+1), Hoskins (68), Rowe (70), Sinclair (86)
West Ham U21s: Baxter, Driver (c), Mpanzu, Spence, Potts (Shaw 46), Bywater (McCallum 69), Moncur, Marlow (Miles 46), Lletget, Lee, Maguire. Subs (not used): Nemrava (GK), Mavila.
Goals: Lee (4), Moncur (pen 29)