In an even encounter devoid of clear-cut chances and quality, second-half strikes from Christopher Nkunku and Dominik Szoboszlai proved to be the difference between the two sides.
Leipzig had almost taken the lead inside the opening four minutes when former Chelsea forward Timo Werner found himself in a surprising amount of space inside the box, with his drilled shot superbly denied by Kevin Trapp's sharp reflexes.
Frankfurt had their own half-chance when Tuta got on the end of Philipp Max's in-swinging direct free kick, but the defender saw his effort inadvertently deflected wide off the foot of a nearby teammate.
The two star French forwards for either side in the form of Nkunku and Randal Kolo Muani both failed to get their first attempts on target during the early exchanges, but Muani's pace and trickery proved to be a constant thorn in the side of Leipzig's defenders, as they would have anticipated prior to kickoff.
The 24-year-old was tugged back by Lukas Klostermann in a dangerous area, before his appeals for a penalty were dismissed after going to ground inside the 18-yard box. Moments later, Nkunku saw another effort tipped wide by Trapp, as the first half drew to a goalless close.
Frankfurt came out after the break as the more threatening team, with World Cup winner Mario Gotze forcing an incredible save from Jan Blaswich, who continues to perform to a high level in the absence of the injured Peter Gulasci.
Ultimately, a little more decisiveness in the final third made the difference, with Nkunku - who may have played his final game for Leipzig ahead of a reported summer transfer switch to Chelsea - firing a deflected effort beyond the helpless Trapp after fine interplay between the France forward and Dani Olmo.
Nkunku was involved once again as Marco Rose's side made sure of their victory five minutes before the end of normal time, as he played in Szoboszlai, who showed great spirit to get to the ball first before slotting the ball into the bottom-left corner from inside the penalty area.
Muani almost pulled a goal back for his side moments later but he was thwarted by the inspired Blaswich, with Rose winning his first trophy in Germany as a manager to make it two cup triumphs for Leipzig in two seasons.
For Frankfurt, they will not have the chance to win their second Europa League title in three seasons, as defeat means they will instead enter the Europa Conference League next time out.