Leverkusen began strongly, and a long ball to Boniface caught the Hoffenheim backline unaware in the 17th minute.
He squared to Martin Terrier from the right flank, allowing the Frenchman to bundle in his first Bundesliga goal at close range.
A second Leverkusen goal always looked likely, and after Oliver Baumann saved a point-blank header from Boniface following a scintillating series of passes, a slicing ball through the Hoffenheim defence from Granit Xhaka put Boniface through.
The Nigerian jinked one way and the other, putting Alexander Prass on the floor and firing low past Baumann for 2-0.
It seemed as though Bayer would cruise from there, but as they did in their last visit here 10 months ago, Die Werkself allowed Hoffenheim a way back.
Before long, Piero Hincapie mistimed an attempted clearance from Andrej Kramaric's low cross from the left, allowing Berisha to net on his first start since undergoing a cruciate operation.
And Hoffenheim momentarily appeared to have drawn level barely two minutes later, as a poor clearance from last November’s matchwinner Alex Grimaldo saw the ball fired straight at Baumann, who could only parry onto Berisha’s head. He couldn’t miss from inches out, but the offside flag put paid to his celebrations.
Leverkusen then nearly restored the two-goal cushion soon after with Boniface going clean through before losing out to Baumann’s snap save, setting the tone for an intriguing second half.
The game lost none of its potential for entertainment, with plenty of cut and thrust as Baumann denied Robert Andrich and Kramaric fired over from a promising free kick just after the hour mark.
If the visitors harboured any fears of losing from a 2-0 lead for a second straight match-week, they hid them well.
Grimaldo in particular was proving a menace on the flanks, nearly playing his part in finishing Hoffenheim off for good, with a cross from the left finding Boniface, who only marginally headed off target.
Grimaldo would play a pivotal role in ending the game as a contest moments later, as he received a flick back from Terrier barely an inch inside the box and was fouled by Dennis Geiger.
A VAR review saw Daniel Schlager award a penalty, which Florian Wirtz fired low into the bottom-left corner.
And Leverkusen eviscerated all remaining doubts just four minutes later, as Boniface went on another searing run through the Hoffenheim defence, dazzling with his fancy footwork and hitting the ball low beyond a helpless Baumann.
It capped off a performance that demonstrated Leverkusen’s deadly ability on the counter, and with this victory, Leverkusen have now scored at least twice in nine of their last 11 away league games. They move back into the top four for now, while Hoffenheim are now 22 Bundesliga home matches without a clean sheet.
Flashscore Man of the Match: Victor Boniface (Bayer Leverkusen)
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