The 25-year-old Poland striker, who will join Bayern Munich at the end of the season, failed to get on the scoresheet in his last home game for Dortmund, but his team-mates stepped up in the Bundesliga’s penultimate round.
In a match of little importance – Dortmund and Hoffenheim had already been assured of finishing second and in mid-table before kick-off respectively – the visitors stormed into an early lead through Roberto Firmino.
However, a Kevin Grossreutz curler, a rare header from Henrikh Mkhitaryan and Lukasz Piszczek’s half-volley ensured Jurgen Klopp's men will enter their final league game of the season at Hertha Berlin with a chance of breaking the 70-point barrier.
Niklas Sule's goal sent nerves through the home crowd, but the day nevertheless belonged to Lewandowski, who joined Dortmund from Lech Poznan in 2010 before firing them to back-to-back Bundesliga crowns.
The Poland international received flowers and a giant poster of himself before kick-off, had his name chanted throughout, and was substituted to a standing ovation in stoppage time.
Dortmund have now scored 17 goals in their last six Bundesliga games, while Hoffenheim's rollercoaster season provided another clash full of highlights.
Klopp claimed he only had "15 fit players" going into the game, but he was able to welcome back left-back Marcel Schmelzer following a groin injury.
Hoffenheim were without suspended second-top scorer Anthony Modeste, but it took their leading marksman just four minutes to break the deadlock.
Kevin Volland's dummy freed Firmino, whose strike from inside the box gave goalkeeper Roman Weidenfeller no chance - the Brazilian grabbing a 15th goal of the Bundesliga season.
It should have been 2-0 on seven minutes. Volland received the ball inside the box and side-stepped Weidenfeller, only to see his close-range strike cleared off the line by the sliding Mats Hummels.
Dortmund turned a deficit into a 3-1 lead with three goals within five minutes around the hour mark.
Sokratis broke up a Hoffenheim attack, carried the ball forward and freed Grossreutz, who curled a fine effort into the bottom corner from the edge of the box.
Just two minutes later, Reus received the ball inside the box, looked up and dinked the ball onto the head of a diving Mkhitaryan, who powered it home.
And Piszczek increased Dortmund's lead after a frantic spell, pouncing on a loose ball and half-volleying the ball just inside the post.
Grosskreutz went close to a second just before the hour, but the visitors retained a threat, Volland's touch deserting him when on goal, allowing Sokratis to intercept.
And Sule did get Hoffenheim back into the game on 65 minutes though. The 18-year-old unleashed a fierce drive from 30 yards which, although directed straight at Weidenfeller, somehow slipped through the FIFA World Cup hopeful’s legs.
Pierre-Emerick Aubameyang’s cross almost gave Lewandowski the chance to score the goal he so desired, but an interception left him on 101 goals in 185 appearances for Dortmund.
And with Dortmund controlling the game in stoppage time, an emotional Lewandowki left the field to a standing ovation and hug from Klopp.
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