: Motivation matters in medical students' academic performance. However, few studies have specifically examined how motivation and external environmental factors (e.g., institutions) affect medical students' performance with large-scale data sets. The roles of self-efficacy and learning engagement in the mechanisms that govern how motivation affects academic performance are still unclear.: This study aims to advance a comprehensive understanding about the relationships between medical students' motivation, self-efficacy, learning engagement, and academic performance in a nationwide survey, taking students' demographic factors and sociocultural environments into consideration.: We collected data from 1930 medical students in China. We probed the relations between studying variables. We then performed structural equation model (SEM) analysis to examine the mediating roles of self-efficacy and learning engagement on the relationship between motivation and academic performance. We further carried out multiple-group SEM analyses to compare differences between males and females, and between students in key universities and colleges (KUCs) and non-key universities and colleges (NKUCs).: Medical students in KUCs demonstrated significantly higher intrinsic motivation, better academic performance and lower extrinsic motivation than those in NKUCs. Male students reported higher intrinsic motivation but surprisingly lower academic performance than females. The total effect of intrinsic motivation on academic performance was larger than that of extrinsic motivation. There were significant indirect effects of either intrinsic or extrinsic motivation on academic performance through learning engagement. Besides, both intrinsic motivation and extrinsic motivation predicted self-efficacy; however, the direct effect of self-efficacy on academic performance was not significant.: This study provided researchers with a holistic picture of students' types of motivation in relation to academic performance. Findings from this study can help in rethinking the role of self-efficacy in medicine, in finding more effective interventions for promoting medical students' levels of motivation, and in developing motivation-related counselling methods for different groups of medical students.