Liam Trotter and Tom Soares scored their first goals for the Dons to inflict a fifth defeat in six league games on the visitors, who were second best throughout.
The hosts went ahead after 27 minutes, when Callum Kennedy’s pinpoint cross was nodded into Trotter’s path by Lyle Taylor and the midfielder had time to compose himself and fire past Mark Oxley.
It was no less than the home side deserved, and they might already have been ahead had Oxley not denied Taylor with a fine save.
Wimbledon doubled their advantage shortly after the break, when Deji Oshilaja’s header was diverted in by Soares, despite a frantic attempt to clear on the goal-line.
Southend did have chances of their own, Marc-Antoine Fortune and Dru Yearwood bringing saves from George Long, while Simon Cox and Jermaine McGlashan both failed to hit the target.
But Wimbledon were good value for their two-goal win and never looked like surrendering it.
Pedro stepped off the bench to send Chelsea into the FA Cup semi-finals after they beat Leicester 2-1 at the King Power Stadium on Sunday evening.
RB Leipzig came from behind at the Red Bull Arena to end a run of four winless games and defeat Bundesliga leaders Bayern Munich 2-1 on Sunday.