Spurs, who desperately needed a win to restore some momentum in north London, had the lead within five minutes, as James Maddison brought down an exceptional Pedro Porro forward ball and finished powerfully to give his side a superb start.
Porro then had a glorious chance to add a second after being played through by Son Heung-min, but he dragged his shot dreadfully wide.
Instead, it was Son who doubled Spurs' lead, with the South Korea international finishing via a deflection in the box after once again getting beyond Hoffenheim's offside trap.
The London club seemed to retreat in the second half, however, and a penalty was awarded on the hour mark, as Brandon Austin came out of his goal to try to reach a cross and made contact with Max Moerstedt. However, a VAR review correctly advised the referee to overturn his decision.
Within five minutes, however, Hoffenheim were back in the game. A quick breakaway saw the Bundesliga side cut through Spurs and Anton Stach finished a fine cross to hand them a lifeline.
But any hope was swiftly extinguished thanks to Son, who completed his brace with a superb finish into the far corner after a quick transition.
Hoffenheim managed to pull another goal back thanks to Mokwa Ntusu's back-post header but it was too late for a grandstand finish.