The Reptile Garden in Brackenridge Park was established in the early 1930s during the Depression. An unemployed herpetologist, W.C. "Bill" Bevan, arrived in San Antonio and found his way to the museum where he was retained to do odd jobs. On learning of his profession, the museum’s director, Ellen Schulz Quillin, suggested that he give snake demonstrations in front of the museum in exchange for donations. He preferred, however, to construct a reptile garden.

Mrs. Quillin took the reptile garden proposal to the City of San Antonio which declined to finance the $750 project. Mayor C.K. Quin , however, gave permission to house snakes in Brackenridge Park in a "safe" enclosure. The all-woman Witte Museum board embraced the proposal, envisioning a money-making project that would sustain the museum during the Depression. Using donated materials and labor, the original reptile garden was constructed of wood planks, barbed wire, and old sheet metal roofing. The published history of the Witte Museum states that this was the first such facility in the United States.

The garden opened on June 8, 1933, and was stocked with rattlesnakes captured on surrounding ranches and bought for 15 cents a pound, alligators purchased at 50 cents a foot, and turtles. Opening night was sponsored by the Junior Chamber of Commerce and the Mayor welcomed visitors. The following day, over 800 people paid 10 cents to view this new curiosity, and within one week, the garden had paid for itself.

Officially known as the Reptile Garden and Research Bureau, the facility attracted both a general family audience and scientists from throughout the world involved in snake bite research. A variety of events drew crowds to the garden including rattlesnake milking, turtle races, and weekly rattlesnake fries. These activities contributed revenue that kept the museum open throughout the Depression.

The reptile garden’s success assured the construction in 1934 of a new, more permanent facility built of limestone with a red tile roof. In its first ten years of operation, Ellen Quillin estimated that 750,000 people visited the Reptile Garden. A drought in the late 1940s created a scarcity of snakes, and the garden’s focus shifted to alligators. The last rattlesnake fry was held on September 14, 1950. The garden continued to be a popular attraction and was managed from 1952 until 1975 by George Kimbrell who collected and displayed alligators and crocodiles. The Reptile Garden closed when Kimbrell retired to Arkansas in 1975, taking his collection with him.