Tranquillo Barnetta gave Armin Veh's men the lead and further goals from Joselu and Alexander Madlung put them in command of the game.
Nuremberg, who had Javier Pinola sent off, mounted a spirited recovery with Josip Drmic and Jose Campana bringing them back to within sight of the draw, but two late goals from Joselu and Vaclav Kadlec sealed Frankfurt's win.
It was a combative opening to the game with some no-nonsense tackling on both sides, but goalmouth action was in short supply.
Tomas Pekhart had the first opening, and he beat Kevin Trapp with his shot but only found the side-netting.
Emanuel Pogatetz lost possession to Stefan Aigner, who had only one thing on his mind as he raced towards the penalty before squaring for Barnetta to net his first goal of the season from close range.
Frankfurt were worthy of their lead but, as they failed to convert a second, Nuremberg were still in the game at the break.
That changed in four minutes early in the second half when first Joselu and then Madlung gave Frankfurt a more comfortable advantage.
Aigner selflessly set up Joselu for his goal, passing rather than shooting with only Raphael Schafer to beat, before Madlung tucked in the rebound after Martin Lanig's header was saved.
Nuremberg did not hoist the white flag, though, and Drmic reduced the arrears in the 64th minute with a great first touch from Campana's pass, and an even better finish.
With less than 20 minutes to go, Nuremberg edged to within one goal of their visitors when Campana scored a stunning goal from fully 30 yards out.
Nuremberg's hopes of finding an equaliser were dealt a blow when Pinola was sent off for fouling Joselu.
The Spaniard then ended Nuremberg's hopes in the 88th minute, volleying in after Schafer saved from Kadlec.
Frankfurt's fifth would come from the Czech striker, though, and he picked his spot in the far corner before curling home a shot with the outside of his boot to leave Nuremberg in the bottom two.