This study examined conscientiousness and the perceived educational environment as independent and interactive predictors of medical students' performance within Biggs' theoretical model of learning. Conscientiousness, the perceived educational environment, and learning approaches were assessed at the beginning of the third year in 268 medical students at the University of Geneva, Switzerland. Performance was examined at the end of the third year via a computer-based assessment (CBA) and the Objective Structured Clinical Examination (OSCE). Path analysis was used to test the proposed model, whereby conscientiousness and the perceived educational environment predicted performance directly and indirectly via students' learning approaches. A second model included interaction effects. The proposed model provided the best fit and explained 45% of the variance in CBA performance, and 23% of the variance in OSCE performance. Conscientiousness positively predicted CBA performance directly (β = 0.19, p < 0.001) and indirectly via a deep learning approach (β = 0.05, p = 0.012). The perceived educational environment positively predicted CBA performance indirectly only (β = 0.02, p = 0.011). Neither conscientiousness nor the perceived educational environment predicted OSCE performance. Model 2 had acceptable, but less optimal fit. In this model, there was a significant crossover interaction effect (β = 0.16, p < 0.01): conscientiousness positively predicted OSCE performance when perceptions of the educational environment were the most positive, but negatively predicted performance when perceptions were the least positive. The findings suggest that both conscientiousness and perceptions of the educational environment predict CBA performance. Research should further examine interactions between personality traits and the medical school environment to inform strategies aimed at improving OSCE performance.