Background: Medical students are known to be subjected to immense stress under competitive curricula and have a high risk of depression, burnout, anxiety and sleep disorders. There is a global trend of switching from norm-referenced assessment (NRA) to criterion-referenced assessment (CRA), and these changes may have influenced the quality of life (QOL), sleep phase, sleep quality, stress, burnout, and depression of the medical students. We hypothesized that there is a significant difference of QOL between CRA and NRA and that sleep, stress, burnout, and depression are the main contributors. Methods: By administering an online survey regarding QOL and its contributors to Korean medical students, 365 responses from 10 medical schools were recorded. To clarify the complex relationship between the multiple factors in play, we applied nonlinear machine learning algorithms and utilized causal structure learning techniques on the survey data. Results: Students with CRA had lower scores in stress (68.16 ± 11.29, 76.03 ± 12.38, P< 0.001), burnout (48.09 ± 11.23, 55.93 ± 13.07, P < 0.001), depression (12.77 ± 9.82, 16.44 ± 11.27, P = 0.003) and higher scores in QOL (95.79 ± 16.20, 89.65 ± 16.28, P < 0.001) compared with students with NRA. Multiple linear regression, permutation importance of the random forest model and the causal structure model showed that depression, stress and burnout are the most influential factors of QOL of medical students. Conclusion Medical students from schools that use CRA showed higher QOL scores, as well as lower burnout, stress and depression when compared with students from schools that use NRA. These results may be used as a basis for granting justification for the transition to CRA.