Introduction <p>Studies on substance use among gay men are often analyzed from the framework of risk and harm, disregarding the user’s perspective about various reasons for use, which for some may not be perceived as potentially harmful. The current study examines substance use among gay men and perceived benefits and adverse effects on their well-being from three unique geographical areas across Mexico.</p> Methods <p>A mixed methods survey and three online focus groups were conducted in May 2022. Nineteen gay men (average age 32&#xa0;years) from northern, central, and southern Mexico participated in the study. Data was interpreted utilizing a content analysis.</p> Results <p>Poppers, crystal meth, and marijuana were the most recently consumed substances, with frequent use reported during sex. First-contact drugs and recreational drugs showed greater perceived social and mental health benefits. In contrast, drugs used during sex had greater perceived adverse effects on overall well-being, primarily with the use of crystal meth.</p> Conclusions <p>There is an apparent ambivalence with using drugs based on the experiences of gay men participating in this study who live in Mexico. Some participants reported an improvement in mental health and emotional well-being, sexual experiences, and increased socialization. Other participants reported harmful effects upon their health, mental health, and social well-being based on decisions to use substances. Implementing a gay-affirming harm reduction model may improve overall health outcomes for this minority population, as well as their mental health, overall well-being, and care needs.</p>