Looking to keep pace with Bayern Munich after their 4-3 win over Holstein Kiel on Saturday, Leverkusen controlled possession from the start, but had to wait until the 15th minute to register a shot - which incidentally found the net.
They worked it from right to left where Alejandro Grimaldo played in Victor Boniface, who struck across goal with his left foot to score just days after his potential move to Al Nassr broke down.
Four minutes later, Jeremie Frimpong made a darting run down the right to collect Aleix Garcia’s long ball, entered the area and hit low into the far corner to double the hosts’ advantage.
Some history was made shortly after that when referee Robin Braun announced the overturning of a penalty - originally awarded to Leverkusen via the BayArena’s PA system - the first time that had happened in the Bundesliga.
Hoffenheim began to improve after that reprieve, and Erencan Yardimci put David Jurasek’s cross into the side netting before Marius Bulter rasped a shot against the gloves of Lukas Hradecky.
Despite some more promise early in the second half, the visitors were pegged back further as new Leverkusen loan signing Emiliano Buendia produced a tricky run into the box, and although his shot was saved, the rebound was smashed in by fellow substitute Patrik Schick - his 14th goal in 10 league matches.
However, the last half-hour was made far trickier when Grimaldo was shown a second yellow card for his challenge on Bulter, and Hoffenheim immediately hit back through Gift Orban, who tapped in among the melee of the resulting free-kick.
But with no immediate second goal, Hoffenheim became increasingly frustrated and ultimately fell short in their comeback efforts.
Having been beaten just once in their last 53 Bundesliga matches, it’s a wonder that Xabi Alonso’s men still have significant work to do if they are to successfully defend their title.
It’s make or break, then, when they face Bayern in two weeks time, while Hoffenheim’s upcoming home match against Union Berlin features the same level of jeopardy - albeit at the other end of the table.
Flashscore Man of the Match: Jeremie Frimpong (Bayer Leverkusen)