Weininger studied at University of Rochester, first at the Eastman School of Music, then switched to chemistry. After graduation, he worked for General Electric in Canada, where he worked on water management. He then attended University of Wisconsin–Madison, where he graduated with a PhD in environmental engineering in 1978. His PhD project involves the study of Polychlorinated biphenyls in Lake Michigan at the University of Wisconsin–Madison. He developed a computational model using data from the United States Environmental Protection Agency (EPA) using computer graphics algorithms, by then still a nascent field.
Upon graduation, he was hired by the EPA directly in its National Water Quality Laboratory in Duluth, Minnesota to develop similar models for other chemicals. During this period, Weininger started working with chemical databases which include structure-activity relationships. Weininger realized the difficulty to balance the IUPAC nomenclature for chemicals, used by human, and the Wiswesser line notation which was more efficient for computer processing. Weininger developed Simplified molecular-input line-entry system, or SMILES, such that it's easy for both humans and computers to understand.
Weininger moved to Pomona College in Claremont, California, working with Corwin Hansch and Albert Leo to work on the prediction of octanol-water partition coefficient (LogP) for molecules, which resulted in the software, cLogP, in 1983. The first publication on SMILES came out in 1988, while Weininger was affiliated with Pomona College.
In 1987, Weininger founded Daylight Chemical Information Systems, Inc. along with his brother Arthur Weininger and the business associate Yosi Taitz.