Reus opened the scoring in the 31st minute and made it 2-0 after 62 minutes. He then set up Igor de Camargo to push the advantage to 3-0 soon after.
Only a year after almost suffering relegation, Gladbach finish the season fourth with a place in the Champions League qualifiers.
And they played like a side worthy of the top four.
The visitors had the first chance of the game after 14 minutes but Mainz keeper Heinz Muller made a fine save against Filip Daems on the counter attack.
The guests were close again 12 minutes later with Muller this time stopping De Camargo from a short distance.
Playing in his final game before moving to Borussia Dortmund next season, Reus scored his first goal of the day in the 31st minute, collecting a pass from Daems and blasting it into the far right corner.
Mainz appeared to have scored a goal eight minutes later through Adam Szalai but the referee gave a foul against him in the build-up.
Reus scored his 18th goal of the season in the 62nd minute to make it 2-0, running onto a through ball from Roman Neustadter and beating Muller.
Muller stopped Alexander Ring from scoring a third Gladbach goal in the 67th minute but the guests finished off the game two minutes later with Reus feeding a through ball to De Camargo, who beat Muller between the legs to make it 3-0.