Nigel Adkins' side are now three points clear of third-placed Huddersfield with a far superior goal difference than the Terriers with one match remaining.
Southampton's top scorer Rickie Lambert took his league tally to 21 goals with two strikes as Argyle's south coast rivals tore into Peter Reid's injury ravaged Pilgrims.
Saints took the lead in the 45th minute when Danny Butterfield's deep cross from the right wing was headed home at the far post by Lambert.
The Saints doubled their advantage in the 49th minute when former Argyle defender Ryan Dickson sidefooted in off the post.
Lambert doubled his tally with a coolly executed 59th-minute penalty before Yannick Bolasie sidefooted home Argyle's consolation goal from 15 yards.
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