Sven Schipplock and Roberto Firmino scored the goals for Markus Gisdol's men as they opened up a six-point advantage over their opponents, for whom Joselu was on target.
All the goals arrived in the second half after a tense opening 45 minutes, and it was the visitors who held the upper hand in Hessen.
Hoffenheim coach Gisdol decided to stick with Jens Grahl in his goal, leaving Koen Casteels on the bench for the first time in the Bundesliga since April and keeping faith with the side which won at Schalke in the DFB-Pokal in midweek.
They looked keen to carry on from where they left off, too, with Firmino trying to set Schipplock up, but an alert Frankfurt defence cleared the early danger.
Hoffenheim continued to show more confidence with Firmino causing plenty of problems and almost giving them them the lead on the half-hour mark, but Kevin Trapp saved his side.
Three goals in the first five minutes of the second half brought the game to life with Hoffenheim taking the lead through Schipplock within a minute of the restart.
Firmino sent through a teasing and tempting ball for his strike partner, who raced through and produced a confident finish.
Hoffenheim's celebrations had barely ended when Joselu brought the hosts level again with Vaclav Kadlec stealing in around the back as Hoffenheim's defence left the ball to go out for a goal kick.
He managed to pull the ball across goal before it went out, and Joselu was provided with an easy tap-in to bring the Eagles level.
Just a handful of minutes passed before Hoffenheim took the lead again with Schipplock and Firmino combining once again, this time in the opposite order with the latter scoring his eighth goal of the season.
Takashi Inui saw a goal ruled out for offside as Frankfurt tried to recover again, but it was Hoffenheim who went closer to scoring a third when Kevin Volland hit the post.