The hosts finished third in the division last term and reached the semi-finals of the Champions League, while Mainz's less eventful season ended with them in 13th place.
The 2019-20 season was the most memorable in Leipzig's short history and they now have to somehow follow that up - a task made all the more difficult following star striker Timo Werner's exit.
Werner has finished as top scorer in all four of Leipzig's Bundesliga seasons so far, meaning that others in the side - such as Yussuf Poulsen, Hwang Hee-chan and Dani Olmo - will have to step up and fill the void.
The aim for Julian Nagelsmann this season will be to once again challenge Bayern Munich and Borussia Dortmund for the title, while also making an impact on the continent in the Champions League.
New signing Hwang made a bright start to his Leipzig career with a goal and an assist in last week's 3-0 win at Nuremberg in round one of the DFB-Pokal.
Mainz also made light work of lower-league opposition in the cup, seeing off Havelse 5-1 in their curtain-raising fixture - Jean-Philippe Mateta helping himself to a hat-trick in that one.
This will be a far tougher test for Die Nullfunfer, of course, and the result of this corresponding fixture last season will still be fresh in the visiting side's memory when they arrive at the Red Bull Arena.
Leipzig ran out 8-0 winners in that match 10 months ago - their biggest ever victory in professional football, as well as being Mainz's worst ever.
The Red Bulls also won the reverse fixture 5-0 and have lost only one of their eight games against Mainz in all competitions.
This is a daunting first test for Mainz, then, especially when you take into consideration that they are without a win in six previous opening weekend matches away from home.
Mainz are also coming off the back of a pretty disappointing pre-season, losing all three friendlies prior to the cup win against Havelse.
Leipzig have had far less preparation time as a result of their 2019-20 season stretching into the second half of August, but Nagelsmann's men will no doubt be ready to go again when that first whistle blows.
RB Leipzig form (all competitions): W
Mainz 05 form (all competitions): W
Leipzig may have lost Werner but they have added the aforementioned Hwang and defender Benjamin Henrichs to their squad, with both players in contention to start this game.
Club captain Marcel Sabitzer ended last season strongly but is a doubt against Mainz because of a thigh problem.
Poulsen is expected to get the nod through the middle and has been directly involved in nine goals in his eight Bundesliga games against Mainz.
Robin Quaison is one to watch for the visitors after scoring 13 league goals in 2019-20 - only three Mainz players have managed more in a single season in their top-flight history.
Leipzig possible starting lineup:
Gulacsi; Klostermann, Upamecano, Halstenberg; Mukiele, Sabitzer, Kampl, Angelino; Olmo, Hwang; Poulsen
Mainz 05 possible starting lineup:
Zentner; Baku, St. Juste, Niakhate, Brosinksi; Barreiro, Latza; Burkardt, Boetius, Quaison; Mateta
We say: RB Leipzig 2-0 Mainz 05
A Werner-less era begins for Leipzig this weekend and, despite the loss of their all-time record scorer, they still boast one of the division's best squads. Mainz conceded 13 goals without scoring against the Red Bulls last season, and we cannot see past a home win on Sunday.