Goals from Neven Subotic, Marco Reus, Pierre-Emerick Aubameyang and Nuri Sahin secured back-to-back league wins for Jurgen Klopp's side - only the second time they have achieved the feat in this troubled season.
Although the hosts dominated the first half, it was Mainz who led at the break thanks to Elkin Soto's volley in the opening minute.
Klopp's half-time team talk obviously had the desired effect, though, as first Subotic and then Reus turned the game on its head in the first 10 minutes of the second period.
Yunus Malli equalised almost immediately for Mainz, but Aubameyang put Dortmund ahead again 19 minutes from time with a well-taken finish from a sublime Reus pass.
And Sahin made certain of the win shortly after, when he followed up Aubameyang's free-kick and converted past Stefanos Kapino.
Victory moves Dortmund up to 14th place in the Bundesliga - level on 22 points with Mainz.
It looked like being another night of misery for Klopp when the visitors opened the scoring inside the first minute as Dortmund's defensive fragility reared its ugly head again.
Subotic failed to clear a lobbed ball into the penalty area, and keeper Roman Weidenfeller could only punch straight to Soto, who lobbed a superb, controlled volley into the unguarded net from outside the area.
Dortmund could have been level two minutes later as Reus found himself in plenty of room inside the penalty area, but his shot thudded against the post and Shinji Kagawa's follow-up was well saved by Kapino.
Finding a way back into the game was proving difficult for Dortmund, but Kagawa went agonisingly close to levelling as the visitors failed to deal with a Reus free-kick.
Dortmund's relentless pursuit of a goal continued after the break and they got their reward within four minutes as Subotic rose to power home Marcel Schmelzer's corner.
And five minutes later the game was turned on its head as Reus celebrated signing a new long-term deal with the club by collecting a perfectly weighted pass from Kevin Kampl before rounding Kapino to score.
Dortmund's delight was short-lived, as Malli and the 22-year-old striker lashed the ball past Weidenfeller from just inside the penalty area a minute later.
But Reus provided a real moment of class to help put his side back in front, with Aubameyang smartly converting his sensational throughball in the 71st minute.
Sahin then slid the ball under Kapino for Dortmund's fourth to give Klopp a vital three points.
