Depressive symptoms and burnout are common among medical students. However, few studies have investigated their trajectory over the course of medical school. Evaluate year-by-year changes in depressive and burnout symptoms over the course of medical school training. Prospective study. Medical students who matriculated at a private medical school inMaryland from 2010 to 2016 (n=758). Clinically significant depressive symptoms were defined as a score of ≥10 on the 9-item Patient Health Questionnaire (PHQ-9), and burnout was measured using the Maslach Burnout Inventory (MBI). High emotional exhaustion, high depersonalization, and low personal accomplishment were defined as scores of ≥ 27, ≥10, and ≤33 on the respective MBI subscales. At matriculation, the prevalences of significant depressive symptoms, high emotional exhaustion, high depersonalization, and low personal accomplishment were 4.3%, 9.4%, 8.6%, and 37.7%, respectively. After adjustment for age, sex, race/ethnicity, marital status, and cohort, compared with year 1, the odds of significant depressive symptoms was significantly higher at the beginning of the 2nd, 3rd, and 4th years of study (ORs=2.63, 2.85, and 3.77, respectively; all ps<0.001). Compared with the 1st year, the odds of high emotional exhaustion also increased during the 2nd, 3rd, and 4th years of study, (ORs=3.46, 4.79, 8.20, respectively; all ps<0.001), as did the odds of high depersonalization (ORs=3.55, 6.14, 12.53, respectively; all ps<0.001). The odds of low personal accomplishment did not significantly differ across years of study. The results of this study suggest that symptoms of depression and burnout may increase during medical school. Because of the high prevalence of depressive symptoms and burnout in medical students, interventions earlier in the medical career pathway that aim to prevent, detect, and treat these symptoms may be of benefit to the physician community.