Goalkeeper Steven Collis made a string of fine saves as Southend claimed a fourth successive league victory and Dean Glover's reign as Vale's caretaker manager started in defeat.
United bossed the early possession, but it was Vale who had the first pop at goal after Adam Barrett's fifth minute foul on Luke Rodgers.
David McGoldrick took the resulting free-kick and his 25-yard effort curled just inches past Collis's left-hand post.
Leon Clarke was off-target with United's first chance, but Vale gradually grew in confidence to dominate much of the play.
Paul Harsley forced a splendid save from Collis after springing the offside trap, then livewire Rodgers went close twice within a couple of minutes.
But Southend rode the storm and took the lead against the run of play in the 32nd minute.
A neat build-up led to Mark Gower laying the ball into the path of Clarke, who put away a fabulous finish with a 25-yard shot which curled high inside Joe Anyon's left-hand post.
Collis again rescued Southend with another reaction save from Harsley's close-range header six minutes later, but the visitors rubbed salt into Vale's wounds on the stroke of half-time.
Gower and Eric Odhiambo were heavily involved in a slick passing move before Alan McCormack fired home from eight yards.
To their credit, Vale again had a real go at the start of the second half as Rodgers and Paul Edwards forced more acrobatics from Collis.
And the pressure paid dividends just before the hour when Rodgers was tripped by Lewis Hunt and then got up to slam in the resulting penalty.
But Southend held firm with no serious concerns after that and Clarke almost extended their lead when his late chip was tipped over by Anyon.