Talented playmaker Toni Kroos scored one goal and set up the other two as he battles for a spot on Germany's World Cup squad.
Second-placed Bayern Munich had provisionally gone top on Saturday after beating Werder Bremen 3-2 to climb to 39 points from 19 matches.
Schalke 04 lost some ground when they squandered a two-goal lead in the last eight minutes against VfL Bochum to draw 2-2 and drop to third place, a further point adrift.
Spectacular Leverkusen, with the league's best attack and defence so far this season, put the hosts on the back foot after only 11 minutes.
Defender Sami Hyypia, completely unmarked, pounced on a deep Kroos free-kick to slip the ball through keeper Timo Hildebrand's legs for the lead.
'SHOWED QUALITY'
"We were careless after taking the lead and gave the opponents hope," said Leverkusen coach Jupp Heynckes.
"At half-time I said we needed to take the initiative and we did that very well and showed our quality. In the second half you could see why we are at the top of the Bundesliga," he told reporters.
The visitors suffered a brief concentration lapse, allowing the hosts to come forward and threaten through striker Vedad Ibisevic who squandered a clear chance five minutes later when he had only keeper Rene Adler to beat.
Hoffenheim teenager Boris Vukcevic then twice saw his shots from the edge of the box fly centimetres wide, the second time in front of an empty goal.
Leverkusen punished their opponents for the missed opportunities, grabbing a second goal six minutes after the restart with Eren Derdiyok beautifully letting the ball slip through his legs for 20-year-old Kroos to net his eighth goal of the season.
Kroos then set up Tranquillo Barnetta for Leverkusen's third goal when he cut into the middle of the box and the Swiss international tapped in from close range in the 71st.
The defeat left Hoffenheim, who have lost the last three league matches, in ninth place on 25 points.
In the day's other match, visitors Cologne dragged themselves away from the relegation zone with a fighting 3-2 victory over champions VfL Wolfsburg which leaves the future of Wolfsburg coach Armin Veh in doubt.
Cologne, in 13th place on 21 points, watched Wolfsburg twice come back from a goal down before Adil Chihi secured their victory with a close-range effort in the 74th minute.
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