Teenage striker Dexter Blackstock came off the bench to score a 30-minute hat-trick as Southampton squeezed through to the last 16 of the Carling Cup.
It took the second-half introduction of substitutes Blackstock and Paul Telfer to change the game after Colchester threatened to cause another Cup upset.
The League One side, who knocked out Premiership side West Brom in the last round, took just six minutes to get in front after Southampton failed to clear Joe Keith's corner, allowing midfielder Neil Danns to head home from six yards.
The visitors' confidence grew and almost doubled their lead on 17 minutes when Sam Stockley's long throw fell kindly to Keith, whose shot from the edge of the area went inches over the bar.
Southampton failed to muster a single shot on target in the first half, but head coach Steve Wigley's double substitution at the break worked wonders.
Substitute Telfer crossed on 50 minutes for Blackstock to toepoke home his first senior goal to get Saints back on level terms.
And just four minutes later the home side found themselves in front when Colchester goalkeeper Dean Gerken spilled Anders Svensson's shot to the feet of Blackstock, who made no mistake from six yards.
But the dogged visitors refused to lie down and got themselves back on level terms just after the hour when defender Claus Lundekvam was dispossessed by Craig Fagan.
The lively striker cut the ball back to Greg Halford, who found the bottom corner with a low left-foot shot.
Lundekvam again got in a mess on 74 minutes allowing Fagan to break through again and set up Halford, only for Jelle Van Damme to make a goal-saving challenge.
And that proved the turning point as Southampton struck a winner ten minutes from the end when another Telfer free-kick found Blackstock at the far post, whose header earned himself a hat-trick and Saints a place in the next round.