The hosts took the lead in this clash, but first-half goals from Marco Reus and the Poland striker ensured another away victory for the reigning champions
Marco Caligiuri opened the scoring with less than five minutes on the clock, propelling a terrific half-volley into the top corner from outside the area.
But less than 10 minutes later Marco Reus equalised when his cross made its way into the bottom corner of the net, before Robert Lewandowski lobbed the visitors into the lead just before half-time.
A third away league victory in a row for the reigning Bundesliga champions ensures they keep in touch with leaders Bayern Munich.
Jurgen Klopp made just one change to the side that swept Ajax aside 4-1 on Wednesday night, with Jakob Blaszczykowski replacing Kevin Grosskreutz.
It was the hosts who started the brighter of the two sides and they stunned Dortmund when Caligiuri lashed home a half-volley from 20 yards out to give the home side the lead.
But the visitors soon began their fightback.
On 11 minutes, Reus found space on the edge of the area and, as Nikolce Noveski dragged Lewandowski away from the ball inside the box, the 20-year-old’s cross sailed into the far corner of the net.
The travelling Dortmund contingent inside the Coface Arena roared back into life, and the visitors started to see more of the ball in the aftermath of the equaliser.
That said, Andreas Ivanschitz then had two wonderful chances to put Mainz ahead for a second time - the first fired straight at the feet of Roman Weidenfeller, and the second bouncing over the crossbar.
With just five minutes of the half remaining Ivanschitz once again failed to finish a gilt-edged chance, when he stabbed a shot wide inside the area.
Those missed opportunities proved costly as Lewandowski lobbed Christian Wetklo to put Dortmund ahead on the stroke of half-time.
The second period continued in a similar vein to the first, with the Poland striker denied a second following Julian Baumgartlinger’s error.
That effort was followed by a lull in play with both sides struggling to create further chances of note and Klopp's men understandably happy with a goal lead.
The home side enjoyed plenty of possession in the latter stages of the half but only had Nikita Rukavytsya's header - with two minutes left - to show for their efforts.
The result leaves Dortmund nine points adrift of leaders Bayern, though the reigning champions do move into second spot at least temporarily, with Schalke taking on Hamburg on Tuesday.