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Self-medication is a common practice among health sciences students, even though legal and educational guidelines promote the rational use of medications. In Mexico, the General Health Law and various studies underscore the need to strengthen health literacy to reduce the risks associated with this practice. To describe the frequency, patterns of self-medication, and associated factors among medical students at a private university in Puebla. A cross-sectional study was conducted with 144 students from the 1st to 8th semester using a 37-item online questionnaire based on previously validated instruments. Absolute and relative frequencies were analyzed, as well as associations using the chi-square test (? = 0.05), considering variables such as gender, semester, reading instructions, and the presence of adverse reactions. Self-medication was prevalent at 91%(n=131). Although 99.3% (n=143) correctly identified the concept and 95.1% (n=137) recognized its risks, the first response to illness was to take a readily available medication (41% n=59). Nonsteroidal anti-inflammatory drugs (NSAIDs) were the most frequently used (75% n=98). The use of scientific sources to decide which medication to take increased with each semester, although choices based on prior experience predominated. Significant associations between gender and self-medication were observed for muscle pain, gastrointestinal pain, vomiting, diarrhea, and allergies (p < 0.05), with greater self-management among men. The most consistent finding was the association between not reading the instructions and experiencing adverse reactions (53.4% vs. 14.1%; p = 0.000001). No significant associations were found with knowing the risks, having medications at home, or receiving family recommendations. Conclusions: Self-medication is highly prevalent, even among students with knowledge of its risks. Although a moderate increase in more informed practices is observed, a discrepancy between knowledge and behavior persists. It is necessary to strengthen educational and social strategies that promote responsible self-medication and the rational use of medications.