The visitors made the breakthrough at the Wirsol Rhein-Neckar Arena as early as the fourth minute when Max Kruse found the target from close range.
The home side were unlucky not to restore parity in the 10th minute when Roberto Firmino saw his shot come off the post.
However, moments later Hoffenheim equalised through Kevin Volland, who fired in from just yards out after finding himself with a loose ball.
Volland scored his second goal of the afternoon in the 26th minute when he latched onto Tobias Weis's pass to slot home from close range.
Julian Schuster came close to equalising for Freiburg in the early minutes of the second half, but saw his header from close range saved.
Igor de Camargo tried to add to the Hoffenheim tally on the hour mark with a shot from the centre of the penalty box, but could not keep it on target.