Background It is not always the sincere or hardworking or intelligent student that gets the highest grades. Exploring unknown dimensions that may distinguish academic performance in adolescents/youth migrating from a high school study environment to that of a professional school and in a learning environment without parental supervision for the first time remains important. We hypothesized that cardiac autonomic activity influenced by cognitive domain factors and emotions would predict academic success in them. Further, we investigated which of their personality traits related to academic performance. Exploratory gender-based analysis was included. Methods A prospective cohort study measured first-year medical students' resting heart rate, heart rate variability (HRV), and personality traits (from the self-reported NEO Five-Factor Inventory-3). Spearman's correlation coefficient tested the correlation between the year-end final aggregate marks and assessed parameters, including subgroup analysis based on gender. Regression analyses of variables with academic marks were performed in the entire cohort. Results The aggregate marks of 81 volunteering students (Mage = 18.7, SD = 0.8 years; 42 females, 39 males) as a cohort did not correlate with their resting heart rate or HRV indices. Subgroup analysis revealed a positive correlation between marks and high-frequency power (r = 0.33, p= 0.03) and total power (r = 0.37, p= 0.02) of HRV in females. The marks positively correlated with the personality conscientiousness score (r = 0.32, p= 0.04) and extraversion score (r = 0.34, p= 0.03) in females.Multivariable regression analysis in the entire cohort revealed no significant interactions. Conclusion Academic performance was significantly related to cardiac autonomic modulation and personality traits of conscientiousness and extraversion in female but not male first-year medical students. These resultsindicate a gender-specific difference in the relation between scholastic performance and HRV in adolescents/youth transiting from high school to professional schools and entering a study environment without parental supervision for the first time. Further our data expands the knowledge base of educational psychology among them.