A win on Thursday, along with a Rubin Kazan triumph over Maribor, will see Owen Coyle's side seal a place in the knockout stage with two group games left to play
Owen Coyle's side were beaten 1-0 at pool leaders Rubin Kazan in their last continental outing, but still sit a point clear of third-placed Zulte with just two games remaining.
A victory at the DW Stadium, coupled with a Rubin win over Maribor, would ensure Wigan's progress into the knock-out rounds.
Zulte, though, go into the match unbeaten in six fixtures in all competitions - a run that has helped them rise to second in the Belgian Pro League.
Francky Dury's men have lost just one of their 16 league games this season, but have been beaten twice in the Europa League.
Wigan, meanwhile, have struggled to juggle league and cup form, and sit 11th in the Championship after Saturday's 1-0 defeat to Brighton.
Striker Marc-Antoine Fortune was disappointed with that loss, and has urged his team-mates to respond on Thursday.
"Bouncing back is the most important thing in football and we've got an opportunity to do that," he said.
"We've got another game on Thursday in the Europa League and it's at home so we have to prove to our fans that we can be much better.
"We're fortunate to have that opportunity and hopefully if we win it can be a boost for both our European and domestic chances."
The visitors have doubts over the fitness of striker Jens Naessens after he limped off towards the end of their 3-1 victory over Mechelen on Saturday. The 22-year-old is suffering from an inflamed tendon in his knee and is unlikely to feature.
Gary Caldwell is one of four players Coyle is set to be without, while the FA Cup winners also have concerns over Ivan Ramis (knee), Scott Carson (ankle) and Shaun Maloney (hip).
The reverse fixture between the sides ended goalless in September.