Cannabis is the most commonly used illicit drug worldwide. In countries with repressive drug policies, the costs of its prohibition plausibly outweigh the benefits. We conduct a cost–benefit analysis of cannabis legalization and regulation in the Czech Republic, taking into consideration alternative scenarios designed using parameters from the known effects of cannabis legalization in selected U.S. states, Canada, and Uruguay. Our analysis focuses on tax revenues, law enforcement costs, the cost of treatment and harm reduction, and the value of Quality Adjusted Life Years (QALYs). Under all the projected scenarios, the identified benefits of legalizing cannabis for personal use exceed the potential costs. The estimated net social benefit of legalization is in the range of 34.4 to 107.6 million EUR per year (or between 3.2 and 10.1 EUR per capita), depending on the size of the cannabis market and the development of cannabis prices after legalization.