Background Prior to the COVID‐19 pandemic, medical students exhibited poorer mental health relative to the general population and other students. This research aimed to assess American medical student mental health during the pandemic's height, while also identifying stressors and vulnerable populations. Methods In this cross‐sectional study, 960 US allopathic and osteopathic medical students completed a mental health survey screening for depression, anxiety, burnout, suicidal ideation and increased substance use during the height of the COVID‐19 pandemic. Potential relationships were explored between these mental health indicators and demographic and environmental factors, such as COVID‐19 exposure. Findings Of the 960 medical students surveyed, 25.1% (n = 241) screened positive for depression, 40.4% (n = 388) screened positive for anxiety, 21.3% (n = 201) met criteria for at least one dimension of burnout, 19.0% (n = 182) started or increased substance use and 7.2% (n = 69) experienced thoughts of self‐harm or suicide. Significant differences (p ≤ 0.01) in measures of mental health were associated with those who had accessed mental health care, had a personal COVID‐19 diagnosis, knew someone who died of COVID‐19 or were female. Conclusions Although rates of anxiety and substance use among medical students in our study were higher than previously reported, rates of burnout and thoughts of self‐harm or suicide were surprisingly lower. These results indicate that some aspects of remote learning imposed by the pandemic could be protective, warranting additional study for post‐pandemic medical education. Meanwhile, medical schools and clerkships should offer additional resources to students particularly vulnerable to stressors, including females and those with personal pandemic impacts.