Third in the table and Champions League semi-finalists last season, pundits in Germany had predicted a tougher ride for Leipzig this year after they sold star striker Werner to Chelsea.
Yet Julian Nagelsmann's side were at their free-flowing best as they started the new campaign in front of 8,500 fans, chalking up 23 shots on their way to a deserved win.
Leipzig have now scored 16 goals in their last three games against Mainz, who are preparing for another relegation dogfight this season.
The home side burst out of the blocks, with both Dani Olmo and Marcel Halstenberg coming within inches of taking the lead in the first few minutes.
The opener came after just a quarter of an hour, as Olmo was tripped by Leandro Barreiro in the box and Emil Forsberg slotted home the resulting penalty.
Danish international Yussuf Poulsen then sent a fizzing shot over the crossbar before doubling the lead with a looping header on 21 minutes.
After Forsberg hit the post on the half-hour mark, it seemed rout was on the cards.
Jean-Philippe Mateta beat the offside trap just after the break to bring Mainz back into the game, but Amadou Haidara linked up with Forsberg just a few minutes later to make it 3-1 and put Leipzig out of reach.