Two goals from Alexander Meier and a Srdjan Lakic strike helped Frankfurt open up a five-point cushion over seventh-place Borussia Monchengladbach.
Dani Schahin pulled a goal back for Fortuna, but they left with a defeat which could see them drop into the bottom three this weekend.
They are ahead of 16th-place Augsburg only on goal difference with the Bavarians in action at Freiburg tomorrow.
Although Schalke's win over Borussia Monchengladbach last night reduced Frankfurt's chances of qualifying for the Champions League next season, they are still in the hunt for the Europa League and, therefore, were as keen as ever for three points.
They took the game to their opponents from the beginning with Meier sending an early warning effort wide of the post.
Another first-time effort from Frankfurt's top goalscorer missed the target as the hosts raised the pressure, resulting in the opening goal on the half-hour mark.
It was a case of third time lucky for Meier, who was on hand to tuck the ball in after Srdjan Lakic's shot was only parried by Fabian Giefer.
Lakic himself was rewarded five minutes into the second half as he doubled Frankfurt's lead with a header from Takashi Inui's corner.
Giefer got a hand to the ball, but he was unable to keep the Croatian's effort out.
Lakic should have made it three on the hour mark, but faced with only Giefer to beat, he tried to lob the Fortuna keeper, who was alert and got his fingertips to the ball.
Fortuna gained belief and pulled a goal back in the 78th minute with Schahin running half the length of the pitch before threading a shot inside the near post.
Frankfurt appeared to be wobbling, but they soon regrouped and, in the 87th minute, put the result beyond any doubt with Meier's 15th and probably best goal of the season.
He received the ball just outside the penalty area and curled it unstoppably into the top corner of Giefer's goal to secure all three points and keep Frankfurt on course for a place in Europe next season.