With Luciano Spalletti having been relieved of his duties as coach, the visitors face an arduous task against Jurgen Klopp's side, who eager to get back to winning ways
Semak was handed control of first-team affairs at Zenit earlier in March following the departure of Luciano Spalletti and will oversee his first Champions League match on Wednesday at Signal Iduna Park.
However, it could well be his last for some time, with Andre Villas-Boas confirmed on Tuesday as Spalletti's long-term successor and Dortmund strong favourites to progress to the quarter-finals.
Things could be much worse for Zenit, given that BVB - last seasons's Champions League runners-up - moved two goals ahead inside six minutes in the first leg of their last-16 tie but Jurgen Klopp's side would have to suffer an unlikely collapse on home turf if the Russians are to progress.
Dortmund have won eight of their last nine Champions League home games, with a 1-0 defeat to Arsenal in this season's group stage the only setback. Zenit, meanwhile, head into Wednesday's game having triumphed in just one of their last seven Russian Premier League matches.
Spalletti's exit followed a goalless draw with Tom Tomsk and Zenit then suffered a 1-0 defeat to CSKA Moscow last time out in Semak's first game at the helm.
Belgian defender Nicolas Lombaerts argues that he and his team-mates must take responsibility for the club's poor form, telling the club's official website: "If the coach is fired, the players should take a look at themselves. In the end, if he was fired, then we're one of the main causes.
"But unfortunately that's the life of a head coach and we have to move on. We're playing for Zenit so we have to do everything to get back on top."
While Dortmund slipped up with defeat on Saturday, they are still a point ahead of third-placed Schalke in the Bundesliga, with the two sides due to meet next Tuesday. They also remain in contention for the DFB-Pokal and history suggests that they will progress to the quarter-finals of the Champions League as well.
In the 12 European ties in which Dortmund have won the first leg away from home, they have triumphed on aggregate 11 times.
Striker Robert Lewandowski has underlined the team's eagerness to bounce back after the loss to Borussia Monchengladbach.
"Of course we can play better," he told Dortmund's official website. "In the end, a draw would have been fair. Now we need to check off the defeat quickly and focus on Zenit St Petersburg on Wednesday."
Klopp could be without Marco Reus, who has missed Dortmund's last three games with a muscle problem, while Zenit's Aleksandr Ryazantsev, a January signing from Rubin Kazan, is not registered for the Champions League and Andrey Arshavin is ruled out through injury.