Substitute Erwin Hoffer turned sharply in the area to score a goal reminiscent of the great Gerd Muller and Takashi Inui added another with a solo effort on the hour to lift Frankfurt above Bayern Munich, who travel to Schalke 04 on Saturday.
Frankfurt, who last topped the standings in 1999, have made the club's best start to a season with a perfect record.
"Twelve points from four games is something that moves us a bit closer to our goal," said Frankfurt coach Armin Veh.
"It is nice to be up there but we know how to look at the situation. There can also be times later on in the season when the situation is completely different."
Confident Frankfurt, having spent one season in the second tier, suffered two early setbacks with striker Olivier Occean and captain Pirmin Schwegler going off injured.
Hoffer, who came on four minutes earlier, scored with a fine strike in the 25th minute before Japan's Inui doubled the lead on the hour after a jinking run past three players.
Nuremberg substitute Sebastian Polter reduced the deficit in the 76th minute with a header past goalkeeper Kevin Trapp.
The hosts twice went close in the final stages but Frankfurt held on to top the table for the first time in 13 years.
