The hosts, meanwhile, are searching for their first win since the end of October as they bid to move into the top half of the table.
Match preview
After playing out a 1-1 draw with Eintracht Frankfurt in their final match before the World Cup break, Mainz returned to Bundesliga action with another draw by the same scoreline away against Stuttgart last weekend.
Marcus Ingvartsen converted from the penalty spot on the stroke of half time, scoring his fifth goal of the season to cancel out a 36th-minute opener from Serhou Guirassy, but the visitors were unable to find a winner in the second half.
Bo Svensson's side have now extended their winless run to five matches and have subsequently slipped to 12th in the Bundesliga table, five points above the bottom three and eight points behind Wednesday's opponents Dortmund in sixth.
Mainz are now preparing for a run of four home fixtures in their next five, but their form in front of their own fans leaves a little to be desired as they have won only one of their last eight games at the MEWA Arena, dating back to May last year.
The 05ers have also lost each of their last five home meetings with Dortmund and will be searching for their first win on home soil against them since September 2014 when they face off on Wednesday.
Dortmund, meanwhile, suffered back-to-back defeats against Wolfsburg and Borussia Monchengladbach before the World Cup break, but they returned to winning ways on Sunday with a thrilling 4-3 victory at home against Augsburg.
The visitors managed to equalise on three occasions, including their third scored by debutant David Colina in the 76th minute, but a stunning volley from Giovanni Reyna just two minutes later ultimately secured maximum points for BVB.
That victory for Edin Terzic's side has boosted their chances of securing a Champions League place for next season as they are now only two points behind the top four, while they are seven points adrift of league leaders Bayern Munich with 18 games still remaining.
While Dortmund have impressed on home soil in recent months, with Sunday's win extending their unbeaten run at Westfalenstadion to nine matches, they have struggled to replicate their performance levels on the road as they have won only three of their last 10 away games in all competitions.
However, BVB will be confident of success at the MEWA Arena on Wednesday, as they have won six and drawn one of their last seven Bundesliga visits to Mainz, scoring at least twice on six of these occasions.
Mainz 05 Bundesliga form:
W
L
L
L
D
D
Borussia Dortmund Bundesliga form:
W
W
W
L
L
W
Borussia Dortmund form (all competitions):
W
L
L
W
W
W
Team News
Mainz will be without Delano Burgzorg (ankle), Jonathan Burkardt (knee) and Marlon Mustapha (thigh) due to injury, while Dominik Kohr will serve a one-match suspension after picking up his fifth yellow card of the season last weekend.
Stefan Bell is able to return from his one-game ban, though, and will likely replace either Anthony Caci or Edimilson Fernandes in the back three, while goalkeeper Robin Zentner should recover in time from a back problem to replace Finn Dahmen between the sticks.
Ingvartsen and Karim Onisiwo, who have scored nine of Mainz's 20 Bundesliga goals so far this season, are expected to continue their partnership in attack.
As for Dortmund, star midfielder Jude Bellingham is the club's only player to have featured for every minute in the Bundesliga so far this season, but the 19-year-old will miss Wednesday's game due to suspension after receiving his fifth yellow card against Augsburg - Mahmoud Dahoud will likely start in centre-midfield as a result.
Meanwhile, Thomas Meunier (muscle) Abdoulaye Kamara and Mateu Morey (both knee) all remain sidelined with injuries, while Marco Reus (illness) and Emre Can (knock), who missed the win over Augsburg, are both doubtful.
Summer signing Sebastian Haller was able to make his long-awaited debut as a substitute on Sunday after recovering from surgery to remove a testicular tumour, and the striker will be in contention to feature again on Wednesday.
Julian Ryerson made his BVB debut last weekend following his transfer from Union Berlin earlier this month, and the right-back is poised to retain his place, while Reyna and 18-year-old Jamie Bynoe-Gittens - who both scored off the bench against Augsburg - will be pushing to start on Wednesday.
Mainz 05 possible starting lineup:
Zentner; Bell, Hack, Caci; Widmer, Barreiro, Stach, Caricol; Jae-sung; Onisiwo, Ingvartsen
Borussia Dortmund possible starting lineup:
Kobel; Ryerson, Hummels, Schlotterbeck, Guerreiro; Dahoud, Ozcan; Adeyemi, Brandt, Reyna; Moukoko
We say: Mainz 05 1-2 Borussia Dortmund
Considering Mainz's home form and Dortmund's recent efforts on the road, a closely-fought contest could be on the cards on Wednesday.