Coach Jurgen Klopp made 10 changes to the side which had downed Real 4-1 last Wednesday, but the outcome was still the same, with Nuri Sahin and Jakub Blaszczykowski on target to practically secure them second place behind Bayern Munich and ahead of Bayer Leverkusen.
Fortuna pulled a goal back through Adam Bodzek in the 88th minute, but it was too little too late as Norbert Meier's side end the weekend level on points with 16th-place Augsburg, ahead of the relegation zone only on goal difference with three games of the season to play.
Only Mats Hummels survived from the Dortmund team which defeated Real in midweek and the central defender, who was building up match practice after a recent injury absence, set up Julian Schieber for the first chance, which the striker headed against the post in the 19th minute.
Just a minute later, the ball was in the back of the net when Leitner passed to Sahin, who looked up and saw Fabian Giefer off his line and lobbed the ball in from fully 35 yards.
Sahin was a constant threat with set pieces, but he was neither able to test Giefer, nor set up a team mate with a succession of free-kicks.
Fortuna tried to get back on terms with Axel Bellinghausen testing Mitchell Langerak in the 64th minute, but the Australian goalkeeper saved his effort.
Blaszczykowski was sent on by Klopp in the 69th minute and, immediately, he doubled Dortmund's lead, latching onto Sahin's fine pass with the outside of his boot to beat Giefer.
Robert Lewandowski was also on the field for Dortmund, given just over 20 minutes to extend his record of having scored in 12 consecutive games.
Marco Reus also came on and he nearly made it three with his first touch of the game in the 80th minute, but Giefer made the save.
Bodzek gave the home team hope with two minutes to go when he headed in Bellinghausen's free-kick, setting up a grandstand finish.
Fortuna searched for an equaliser while Lewandowski went close to making it three for a Dortmund side who held on to all three points ahead of their biggest game of the season so far on Tuesday.