Highlight: MK Dons 0-6 Southampton: Easy progress for Koeman's side
The hosts had knocked out Premier League clubs three times in the past five years in this competition, including last season's 4-0 defeat of Manchester United, but were blown away by a strong, attacking Southampton side.
Rodriguez scored with the first shot of the game after just five minutes, sprinting clear of a desperately scrambling home defence before curling past David Martin from the edge of the box.
The lead was doubled five minutes later as Mane was given acres of space to run into on the counter-attack and he confidently dinked the ball over Martin.
Karl Robinson's side failed to heed the warning and their high defensive line was caught out again when Long raced onto a ball over the top and squared for Mane to make it three goals from as many shots on target.
Southampton showed no less urgency after the break and Rodriguez bagged a quick goal once again, converting from the spot after Kyle McFadzean felled Long.
Virgil Van Dijk saw his free-kick clip the crossbar on its way over after 56 minutes and Lee Hodson's last-ditch defending denied Rodriguez his first competitive hat-trick moments later.
McFadzean's bad night continued as he cut out Juanmi's cross for Rodriguez, only for his clearance bounce back off Long – who knew nothing about it – and loop into the net.
There was nothing fortuitous about Long's second as the striker hammered into the top corner after again beating the hosts' offside trap to get onto Steven Davis' throughball.
Rodriguez thought he had a third for Ronald Koeman's men nine minutes from time, but his bottom-corner strike was ruled out for offside, though it mattered little come the final whistle.
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