Objective: To explore the role of personality traits in at-risk drinking and current cannabis use among medical students. Methods: This cross-sectional study evaluated 707 medical students from two universities. Multiple logistic regression models for at-risk drinking and current cannabis use were constructed including sociodemographic, psychiatric, and personality variables. Results: At-risk drinking and current cannabis use were reported by 19.3% and 14.9% of participants, respectively. Models including Big Five measures showed associations of at-risk drinking with higher extraversion (p < 0.00001, adjusted odds ratio [AOR] = 1.9) and lower conscientiousness (p = 0.00001, AOR = 0.5); cannabis use was also associated with lower conscientiousness (p = 0.003, AOR = 0.6), besides higher openness to experience (p = 0.002, AOR = 1.9). Models including measures of the Behavioral Inhibition and Activation Systems scales (BIS/BAS) showed associations of at-risk drinking with lower BIS (p = 0.002, AOR = 0.9) and higher BAS fun-seeking (p = 0.0005, AOR = 1.2); cannabis use was also associated with higher BAS fun-seeking (p = 0.008, AOR = 1.2). Personality variables had modest effects on model fit. Conclusion: Specific personality traits were independently associated with at-risk drinking and current cannabis use, albeit with modest effect sizes.