The Botanic Garden at Johannes Gutenberg University Mainz was laid out between 1946 - 1955. The site on which it stands was used for agriculture and planted with fruit trees; some parts were also used for military exercises. In the difficult economic conditions of the post-war era, it was the garden staff and students who had to develop the site themselves. The founder and first director of Mainz Botanic Garden was the botanist Prof. Dr. Wilhelm Troll (1897–1978). He was helped with the design of the garden by Max Top (1895-1986), the garden's first Technical Director.

The main concept underlying the formation of the garden was to make plants available to the university – for teaching and research purposes. Wilhelm Troll's main interests were the comparative morphology of the different plant groups. To cultivate material for his broadly-based studies, a large systematic facility was created at the center of the outdoor area consisting of over 3,500 individual beds. The plants were grouped according to relationship-related criteria. By the mid 1950s, the alpine facility and a large pergola in the biological section were completed. In 1986, the garden was extended and a steppe ecoregion and a reproduction of the "Mainzer Sand" nature reserve terrain were added. In 2006, during a major redesign of the garden, the steppe vegetation was moved to the center of the gardenp>

The first greenhouse was built in 1948; two more secondhand greenhouses were acquired in 1952. The tallest greenhouse to date, known as the "Verbinder" (House 13), was obtained in 1954. While the open air spaces of the Botanic Garden were open to visitors from the start, the greenhouses were never intended as "show houses." Only in the early 1990s were these opened to students and visitors by the then Garden Director Prof. Joachim W. Kadereit, PhD.