Helmes scored both goals as Hoffenheim were humbled at home for the first time at the Rhein-Neckar-Arena which opened in January.
"We knew that we had to put our opponents on the back foot," said Bayer
coach Bruno Labbadia. "We wanted to be the first team to beat Hoffenheim here and I am happy for the team that we achieved that. It was important for us to know we can beat any team in the league."
The league leaders are now in danger of losing their place at the top to Bayern Munich or Hertha Berlin on Saturday. They lead by just a point from Bayern with Bayer Leverkusen now up to fourth and just three points off the leaders.
"We made too many errors, which is not typical of us," said Hoffenheim
coach Ralf Rangnick. "We conceded two goals in the first ten minutes. There were a few key passages of play for us, above all the goals just before and after half-time. It is crucial now to see how the team responds in our next game against Stuttgart."
Leverkusen took the lead after Hoffenheim's defence allowed Bayer's Brazilian Renato Augusto to slide a cross into Helmes who showed clinical finishing and buried his shot in the back of the net after three minutes.
Hoffenheim were 2-0 down just eight minutes later when a goal-mouth scramble saw Bayer captain Simon Rolfes stab his shot home. But the home side fought back thanks to a helping hand from Bayer's Germany goalkeeper Rene Adler.
Adler made a hash of his tackle on Senegal striker Demba Ba, earning himself a yellow card and conceded a penalty simultaneously with half an hour gone. Midfielder Sejad Salihovic made no mistake with the spot kick.
But Hoffenheim fell further behind just before the half-time whistle when Helmes again received a crisp pass in front of goal and made no mistake in beating former Germany goalkeeper Timo Hildebrand to make it 3-1 at the break.
Leverkusen ensured it had the three points when ex-Germany defender Gonzalo
Castro lobbed his header over Hildebrand on 48 minutes.
With Bayern Munich playing Hertha Berlin at the capital city's Olympic Stadium on Saturday, the winner of that game will go top of the league.