Wolfsburg finished seventh last season and have won-back-to-back games to begin this new campaign, while Leverkusen finished fifth last time out and will be aiming to go one better this term.
Leverkusen were left to rue their luck in June as they missed out on a Champions League spot to Borussia Monchengladbach despite registering 63 points - the first time in the three-points-per-win era where that tally has not been enough to finish at least fourth.
Peter Bosz's side now have to settle for the Europa League, which is also the case for opponents Wolfsburg after holding off Freiburg to seal a place in the second-qualifying round.
The Wolves made a positive start to their European adventure on Thursday by cruising to a 4-0 win over Albanian side Kukesi, with Wout Weghorst helping himself to a couple of goals either side of half time.
Wolfsburg will now play Desna Chernihiv in the next round, though Oliver Glasner will not be all that happy to have so many fixtures crammed into the first month of the new campaign.
Glasner's charges have also already brushed aside Union Furstenwalde in the first round of the DFB-Pokal, making it six wins in a row for them when taking friendlies into account.
All focus now is on this Bundesliga opener with Leverkusen - the third time the sides have met on matchday one, with this weekend's visitors claiming victory on both previous occasions.
Die Werkself have played just the one competitive game in 2020-21, overcoming Eintracht Norderstedt 7-0 in last week's DFB-Pokal opener, though their previous campaign stretched into August after reaching the Europa League quarter-finals.
A defeat to Inter Milan brought down the curtain on a positive season, but matching that success will be a lot tougher now that Kai Havertz and Kevin Volland have left for Chelsea and Monaco respectively.
Patrick Schick has been brought in and will be under a bit of pressure to hit the ground running as Leverkusen look to make a fast start to the season.
Bosz's side have won their last four away league meetings with Wolfsburg, most recently picking up a 2-0 win at the Volkswagen Arena last November.
Wolfsburg form (all competitions): WW
Bayer Leverkusen form (all competitions): W
Weghorst played a massive part in Wolfsburg's seventh-placed finish last season with his 20 goals - a tally bettered by just three other players in the division.
As for Leverkusen, Schick impressed on loan with RB Leipzig last season and will almost certainly lead the line this weekend.
Wolfsburg possible starting lineup:
Casteels; Klaus, Lacroix, Brooks, Otavio; Schlager, Arnold; Steffen, Mehmedi, Brekalo; Weghorst
Bayer Leverkusen possible starting lineup:
Hradecky; L. Bender, S. Bender, Tapsoba, Sinkgraven; Wirtz, Aranguiz, Demirbay; Amiri, Schick, Diaby
We say: Wolfsburg 1-2 Bayer Leverkusen
Wolfsburg beat Leverkusen 4-1 towards the end of last season, but that is just one of two victories for the Wolves in their last nine Bundesliga meetings with this weekend's opponents.
Leverkusen may have sold a couple of important players during the summer but they still have plenty of talent in their ranks.
That, combined with the fact Wolfsburg had a game in midweek, means we are backing the visitors to win this one.