Southampton effectively won promotion to the Championship with a victory at Plymouth which also condemned Argyle to relegation from League One.
Rickie Lambert headed the Saints ahead before Ryan Dickson sidefooted home.
Lambert made it three from the spot after being fouled by Curtis Nelson, before Yannick Bolasie's consolation.
The win means Southampton lead third-placed Huddersfield by three points with one game left and also enjoy a vastly superior goal difference.
It will now take an improbable 17-goal swing on the final day of the season to deny the Saints, leaving the Terriers to try their luck in the play-offs.
But, for Argyle, League Two looms after a second successive relegation, one which always looked on the cards from the moment they were docked 10 points in February for issuing a notice of intention to appoint an administrator.
Saints tore into Peter Reid's Pilgrims from the off but had to wait until the stroke of half-time for their breakthrough when Lambert headed home Danny Butterfield's deep cross at the far post.
Any nerves they had were eased further four minutes after the interval when defender Dickson slotted in off the post from Adam Lallana's cross just seconds after Plymouth had survived a goalmouth scramble when Radhi Jaidi's header came back off the upright.
And promotion was all but guaranteed when Lambert coolly fired in his 21st goal of the season from the penalty spot.
David Connolly was denied a fourth when his 30-yard strike cannoned back off the underside of the bar, leaving Bolasie to have the final say when he sidefooted home from 15 yards deep into stoppage time.