Bayern Munich and Hertha Berlin will battle to take over at the top when the second and third-placed teams, one and two points behind Hoffenheim respectively, meet on Sunday.
Hoffenheim, who suffered a first home defeat of the season, never really managed to find their footing after Leverkusen opened up a 2-0 lead in just 12 minutes with lightning-quick attacks that rattled a shaky home defence.
"We have to ask ourselves if we were in the wrong movie after 2-0 because had we used our chances better we could have got something out of this," Hoffenheim coach Ralf Rangnick told reporters while acknowledging Leverkusen deserved to win.
Helmes grabbed a first-half brace, taking the Bundesliga's second-top scorer this season to 15 goals, with Simon Rolfes and Gonzalo Castro also on the scoresheet for the visitors.
Hoffenheim had briefly reduced the deficit to 2-1 with a well-struck Sejad Salihovic penalty just past the half-hour mark after Demba Ba was brought down by home keeper Rene Adler.
They also conceded five goals against Leverkusen in their first league encounter back in August.
DIFFICULT CONDITIONS
With the temperature below freezing and snow falling throughout most of the first half, conditions were difficult but with two of the league's most attack-minded teams on the pitch it was never going to be a low-scoring affair.
The visitors stunned Hoffenheim after three minutes when Renato Augusto found Helmes unmarked on the edge of the box and the Germany striker fired past keeper Timo Hildebrand.
Before the hosts could regroup Leverkusen struck again through Simon Rolfes.
Tranquillo Barnetta floated a free kick into the box and Hoffenheim failed to clear before Helmes fed Rolfes who knocked the ball away from Hildebrand and slotted it home.
The hosts pulled one back in the 31st with Salihovic's penalty but deep in first half stoppage time Helmes bagged his second of the night after a well-executed free kick combination involving Stefan Kiessling, Barnetta and Michal Kadlec.
The visitors picked up where they left off, adding a fourth two minutes into the second half when Gonzalo Castro outjumped a static Hoffenheim defence to head the ball into the net.
Hoffenheim are top with 39 points from 20 games followed by Bayern and Hertha while Leverkusen are up to fourth spot level on 36 points with Hamburg, who host Arminia Bielefeld on Sunday.
