Lucien Favre's men sit third in the German top flight but are only two points clear of seventh-placed Bayern Munich and must win to ensure they remain ahead of the chasing pack and keep the pressure on the top two.
Mainz have endured a difficult start to their Bundesliga campaign and are 13th, just three points clear of a relegation playoff place.
There have been signs of improvement for the struggling side of late with two wins from their last three games - their first back-to-back wins of the season.
However, Achim Beierlorzer's side, who have yet to draw a game this term, have suffered nine defeats in their 14 games so far - the most of any team outside the relegation zone.
Dortmund, on the other hand, have the joint-fewest losses in the division, losing just twice domestically, alongside second-placed RB Leipzig.
In addition, Farve's side have won their last two league outings, the most recent of which was a 5-0 thumping of Fortuna Dusseldorf.
Dortmund are also the third-highest scorers in the league, behind Leipzig and Bayern, while Mainz have the worst defensive record, conceding 34 times in just 14 games.
All this should give Dortmund plenty of encouragement as they look to capitalise on a sub-par season from the usually-dominant Bayern and claim the Bundesliga crown for the first time since 2012.
However, the favourites will have to guard against ill-discipline, having had a man sent off in two of their last three games across all competitions.
Mainz 05 Bundesliga form: WLLWWL
Borussia Dortmund Bundesliga form: WLDLWW
Borussia Dortmund form (all competitions): LDLWWW
Favre will be without three key players as his Dortmund squad travel to Mainz on Saturday.
The Swiss coach's biggest problem lies in midfield, however. Thomas Delaney has torn ligaments in his ankle and Axel Witsel is out until the new year with a facial injury, leaving Dortmund very light in the middle of the park.
Mainz 05 possible starting lineup:
Zentner; St. Juste, Fernandes, Niakhate; Brosinski, Kunde, Baku, Martin; Boetius; Quaison, Onisiwo
Borussia Dortmund possible starting lineup:
Burki; Akanji, Hummels, Zagadou; Hakimi, Weigl, Brandt, Guerreiro; Hazard, Reus, Sancho
We say: Mainz 05 0-5 Borussia Dortmund
Mainz have conceded a combined total of 17 goals from their three games against Bayern and current top two Leipzig and Borussia Monchengladbach - three of the four sides to have hit at least 30 league goals this term. Dortmund are the fourth and, given the porous nature of Mainz's defence, could help themselves to a big win akin to the one they recorded against Dusseldorf at the start of the month.