A last-minute goal from Barry Hayles gave Plymouth a thoroughly-deserved victory over Southend, who move a step closer to relegation from the Coca-Cola Championship as a result.
Peter Clarke's 25th-minute equaliser had looked like being a lifeline for United after Sylvan Ebanks-Blake had opened the scoring for the home side early on.
But after hitting the woodwork through both Ebanks-Blake and Akos Buzsaky, Hayles popped up in the dying seconds to deny Southend what would have been a vital point.
The home side flew out of the blocks and were ahead after only five minutes.
Peter Halmosi supplied the opportunity from the left of the penalty area and Ebanks-Blake steered the ball home with his right foot from close range.
The visitors threatened for the first time three minutes later when Steven Hammell's inswinging corner was met by the head of Simon Francis, but he could not keep it down and the ball cleared the crossbar.
Two minutes later Freddy Eastwood tried his luck from 12 yards but Luke McCormick was on hand to parry the ball to safety.
Southend were forced into a reshuffle after just 12 minutes when the injured Mark Gower was replaced by Richie Foran.
The visitors then had a half-chance through Halmosi, only for Darryl Flahavan to make the save, before Lilian Nalis shot wide from a good position.
Ebanks-Blake headed just over midway through the first half before the visitors got back on level terms through Clarke.
Hammell swung a free-kick in from the right wing and Clarke headed into the roof of the net from close range.
Ebanks-Blake was continuing to cause problems for the Southend defence and the former Manchester United man had another shot well saved by Flahavan after 33 minutes.
He went even closer a minute later, when his drilled effort from 12 yards hit the post and went behind for a goalkick.
Buzsaky fired in a shot from 35 yards that Flahavan parried, and the keeper then repelled another shot from Hayles.
Ebanks-Blake blasted wide and Buzsaky cracked the crossbar from distance as Southend held on for half-time.
Plymouth started the second period in the same vein and Flahavan was quickly called into action to save from Hayles and Halmosi and, just before the hour mark, he again saved his side after Marcel Seip got his head to a Halmosi free-kick.
On a rare attack of their own Southend threatened through Lee Bradbury, only for McCormick to make the comfortable save.
David Norris was the next to be denied by Flahavan before Argyle threw on Kevin Gallen for Ebanks-Blake with five minutes left to try and shake things up.
And Ian Holloway's switch reaped instant dividends when Gallen supplied the pass for Hayles to fire home from 12 yards with seconds left to the delight of the home faithful.
Teams
Plymouth McCormick, Connolly, Doumbe, Seip, Sawyer,Buzsaky (Gosling 82), Norris, Nalis, Halmosi (Timar 90),Ebanks-Blake (Gallen 86), Hayles.
Subs Not Used: Larrieu, Fallon.
Booked: Buzsaky, Sawyer.
Goals: Ebanks-Blake 6, Hayles 90.
Southend Flahavan, Francis, Clarke, Barrett, Hammell,Campbell-Ryce, McCormack, Maher, Gower (Foran 13),Eastwood (Harrold 75), Bradbury.
Subs Not Used: Collis, Hunt, Moussa.
Booked: Bradbury, Maher, Hammell.
Goals: Clarke 25.
Att: 11,097
Ref: Paul Armstrong (Berkshire).