Andrew Fleming's brace saw the visitors come out on top despite having substitute Robbie Threlfall sent off with 20 minutes remaining.
And that made it seven games against the Shrimpers without defeat for Jim Bentley's side since their first meeting in 2010, while Phil Brown's side also fell to a third successive defeat this term.
Southend were initially on top with Freddy Eastwood heading against a post from 12 yards.
The home side then went in front of the half-hour mark when fit-again Kevan Hurst sent a deflected left-footed shot in to the bottom corner.
But Morecambe were back level five minutes later when Fleming fired home from 20 yards.
The midfielder then put the Shrimps ahead 17 seconds into the second half as he lashed home from just inside the penalty area after Daniel Bentley had denied Padraig Amond.
Jack Sampson, a former Southend loanee, then netted a deflected shot from 25 yards which enabled Morecambe to come out on top, despite Threlfall seeing red for a poorly timed challenge on Anthony Straker.