Having been beaten 1-0 in the first leg, Hull needed a convincing win at home but while Robbie Brady’s brace was enough to ensure a 2-1 victory on the night, Jordan Remacle’s strike proved crucial in separating the sides.
The Tigers’ hopes of finding an all-important third that would have swung the game back in their favour went up in smoke in the 72nd minute when Ivorian striker Yannick Sagbo was sent off.
With 10 men the task proved too much for Steve Bruce’s side but there was late drama as Tom Huddlestone’s late strike – the last kick of the game – was blocked on the line by defender Alexander Scholz.
Bruce had gambled with his team selection, ever mindful not to compromise the Barclays Premier League campaign, leaving the likes of Huddlestone, Nikica Jelavic and Tom Ince out of his starting XI amid six changes from the weekend draw with Stoke.
All three came on as second-half substitutes but it was one of the players who had been rotated in, Brady, who did most to further the Hull cause.
He bundled home after just six minutes for his first goal in nearly a year and, after Remacle’s well-struck equaliser, restored the lead with a cool penalty nine minutes into the second half.
But in truth Hull have not looked the part in any of their four European outings to date, edging past Slovakia’s AS Trencin then making a mountain out what had seemed a favourable play-off draw.
The evening had started so well for the hosts, with Brady starting and finishing the first real chance of the match.
He won the ball just inside the Lokeren half before offloading to David Meyler and heading off in search of the penalty area.
Brady was waiting at the far post by the time the ball was spread wide to Maynor Figueroa, whose curling cross bounced awkwardly but should never had escaped goalkeeper Jerry Verhulst or his defence.
Brady merely allowed the ball to bounce off him and into an empty net before roaring off in celebration.
That was as good as things got in the first half, though, with a series of picky refereeing decisions and just as many offside flags against Sagbo stripping Hull of any rhythm.
Lokeren, on the other hand, gradually found their feet.
After 16 minutes last week’s match-winner Hans Vanaken met Scholz’s cross on the volley but it was a scuffed connection and Curtis Davies was on hand to block it six yards from goal.
Hull were sitting too deep and inviting pressure but clear chances were scarce.
With half-time looming they finally got going again, Figueroa and Brady teaming up on the left before the latter’s cross was headed clear at the near post.
Sagbo won the battle for the second ball and invited Meyler to volley from the edge of the area, with the Irishman’s dipping effort drawing an athletic diving save.
Lokeren immediately reclaimed the initiative after the interval and within five minutes had the equaliser.
A free-kick routine that ended with a Killian Overmeire piledriver earned a corner and when that was only half-cleared, Nill Depauw spotted Remacle in space.
His right-footed effort found a small gap between the man on the post and an unsighted Allan McGregor, the away goal immediately shifting the balance of power.
Hull needed to get back into it fast and did so in the 54th minute.
Ahmed Elmohamady’s cross from the right was blocked by the first man and, with the Egyptian screaming for handball, the officials eventually awarded the spot-kick.
Brady won the argument with Sabgo to take it and placed his shot calmly into the corner.
Hull were ahead on the night but still in needed of another when Lokeren defender Scholz scrambled the ball past McGregor only for an earlier foul by Koen Persoons to cost his side the goal.
The game was becoming stretched at both ends, with a pair of gilt-edged chances going begging.
First Hull substitute Jelavic headed Elmohamady’s cross wide while ummarked from six yards, then Depauw wasted a glorious opening with a tame finish.
But Hull’s chances of an all-important third tumbled with 18 minutes left, Sagbo seeing red for going over the top in a challenge with Giorgios Galitsios.
The arrival of Ince and Huddlestone from the bench raised Hull’s game, with an unsuccessful penalty appeal and Huddlestone’s charged down shot both briefly raising hopes of a decisive third.