Southampton hover one point above the drop zone after Plymouth handed them a fourth straight Championship defeat.
After a bright start for both sides, Plymouth took the lead when Rory Fallon headed home Craig Noone's pass.
Argyle doubled their lead after half-time when Olly Lancashire was judged to have handled Fallon's shot and Luke Summerfield converted the penalty.
Noone hit the post as Plymouth pressed forward while Ryan Smith's long-range effort was the best effort for Saints.
Plymouth boss Paul Sturrock: "I must admit I would have felt aggrieved if the penalty had gone against us.
"But you take what you get and obviously there is a relief around the place that we have now got that win under our belts.
"We needed a win, but I thought we played better when we lost to Birmingham and in the second half against QPR than we did today - and yet from those two home games we only got a point."
Saints boss Jan Poortvliet:
"It is unusual for my players to react like that. If they think it is a penalty they would not have said anything. They felt it was Olly's head the ball hit, not his hands.
"We still tried to play football and we hit the post. We did not create that many chances today but I thought in the second half especially we tried playing football."
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