Ex-Chairboys midfielder Anthony Grant had threatened to spoil the party when he blasted the Shrimpers ahead early on, but goals from Scott Donnelly, Ben Strevens and Scott Rendell sparked wild celebrations as Wanderers finished a point clear of fourth-placed Shrewsbury - a year after they were relegated to the fourth tier.
Southend started brightly and Grant capped a slick break to put them ahead after 15 minutes, firing a deflected shot into the corner of the net past Nikki Bull from the edge of the box.
Bull then pushed wide Ryan Hall's fierce long-range drive before Donnelly equalised for Wycombe in the 26th minute, collecting Stuart Lewis' defence-splitting flick to fire low past Glenn Morris from 12 yards.
Strevens put the Chairboys in front just six minutes later when he poked home the loose from close range after Morris had flapped at Danny Foster's cross.
And Rendell sealed Wanderers' third straight win when the striker curled a neat first-time finish inside the far post from 12 yards eight minutes after the break.