Goals from Liam Dickinson and Peter Gilbert moved Southend into the play-off places as Plymouth suffered their eighth successive league defeat.
Dickinson put the Shrimpers ahead when he converted a penalty after Durrell Berry had fouled Michael Timlin.
Things then got worse for the Pilgrims as captain Carl Fletcher was shown a straight red card for grabbing Timlin.
Gilbert scored against his former side, his first goal since October 2003, with a close-range header to seal the win.
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Southend United manager Paul Sturrock told BBC Essex:
"The first half wasn't pleasing, it wasn't the standards we were wanting to achieve.
"The second half, after a blast, we came out and showed enthusiasm.
"We were a lot better, we got ourselves in the right areas and created a load of chances."
Plymouth manager Peter Reid told BBC Radio Devon:
"When they got the penalty we always knew it was going to be difficult.
"As much as we huffed and puffed it wasn't to be today.
"You have to have a desire to get into those positions and score goals and we didn't."