Vine bagged goals number six and seven of the season either side of the interval after the U's had taken the lead in front of Hatters' biggest home crowd of the season.
The Pompey loan forward's brace was cancelled out as Greg Halford nodded an equaliser just after the hour and Colchester finished the game the stronger.
Luton started brightly and Sol Davis saw a 20-yard strike deflected just over the bar off Wayne Brown's head in the fifth minute after Peter Holmes' cross had been half blocked.
Chris Coyne let fly in the seventh minute when his 25-yard piledriver from Kevin Foley's pass whistled just past Aidan Davison's right-hand post.
Colchester's first opportunity came in the 18th minute when Sam Stockley burst into the penalty area and laid off to Gavin Johnson, who fired well wide.
The Hatters should have gone in front in the 23rd minute when Howard's 16-yard shot from Vine's pull back was parried by Davison, but Vine could only hit the top of the bar from four yards out after being first to the loose ball.
Instead it was Colchester who took the lead out of nothing in the 34th minute when Craig Fagan crossed dangerously into the penalty area and as Robinson and Richard Garcia challenged, the ball spun past Marlon Beresford into the bottom corner.
But Town were level three minutes later when Kevin Nicholls' cross fell to Holmes, whose shot deflected into the path of Vine to stroke home from six yards against his former club.
Three minutes after the break Vine got his second when Nicholls charged into the box after a one-two with Howard and after the Town skipper's shot was blocked by Davison, Vine followed up to fire home from nine yards.
Colchester equalised in the 62nd minute when Davison's long punt upfield fell for Halford to nod past the stranded Beresford from the edge of the area.