The home side made the perfect start as they took the lead with only six minutes on the clock.
A ball over the top into space gave Nebel the chance to break into the area, and his right-footed effort took a slight touch off the outstretched Arthur Theate to lift it over the helpless Michael Zetterer and into the net.
A league-high 11 of Frankfurt’s 13 Bundesliga away matches this season had seen both sides score prior to kick-off, and they added to that tally midway through the half.
Jean-Matteo Bahoya got the better of his man and squared to Nathaniel Brown from near to the byline, and the left-back’s first-time finish from 10 yards out beat Daniel Batz.
Mainz almost restored their advantage just three minutes later when Kaishu Sano's low, driven effort from range went just wide of the left post with Zetterer scrambling to get across.
After a pretty even first half, there was a heart-in-mouth moment for the hosts two minutes before the interval when a low cross into the area was almost turned into the Mainz net by defender Dominik Kohr - instead, though, the ball just evaded the target.
Urs Fischer's men were still on a high after reaching the quarter-finals of a UEFA competition - the UEFA Conference League in this case - for the first time in their history on Thursday, and they were competing well against a Frankfurt side who had collected 11 points from new boss Albert Riera’s first six games in charge.
Ritsu Doan was lively all afternoon for Die Adler, and he almost set up Fares Chaibi just after the hour mark, with the Japanese winger’s cross into the area headed onto the crossbar by the Algerian. Shortly after, Dōan went close to finding the net himself when his first-time effort from the right side of the area was pushed around the post by Batz.
The hosts looked set to be awarded a penalty with just over 10 minutes remaining when Sheraldo Becker went down inside the area, but after consulting the pitchside monitor, referee Tobias Stieler spotted a foul in the build-up.
However, in a dramatic conclusion, Becker saw his effort from inside the area hit both posts, before Nebel popped up with a minute of normal time remaining to snatch the spoils.
Nelson Weiper’s close-range header was saved by Zetterer, but the midfielder was on hand to bury the rebound and spark scenes of wild celebration from the jubilant home fans.
Mainz saw out the game’s remainder to climb three places to 11th, opening up a six-point buffer to the relegation zone in the process. Dejected Frankfurt, meanwhile, remain seventh, eight points adrift of the final European place with seven games remaining.