Objective: To compare mental health indicators among undergraduates in Fall 2019, before the COVID-19 pandemic, and Fall 2020, when many students returned to campus amidst restrictions on in-person contact. Participants: Analyses included 26,881 undergraduate students, aged 18-24, from 70 U.S. institutions. Methods: Students completed the National College Health Assessment-III survey in Fall 2019 or Fall 2020. Results: The prevalences of high stress, loneliness, a low flourishing score, and serious psychological distress increased in 2020 compared to 2019. Serious psychological distress increased substantially in 2020 among students not living with family (adjusted prevalence ratio (aPR)=1.36, 95% CI 1.29-1.45) but not among students living with family (aPR = 1.09, 95% CI 0.95-1.26). Conclusions: These results suggest prevalences of several indicators of poor mental health were elevated among U.S. undergraduates several months into the pandemic. The pandemic may have had greater impact on mental health among students not living with family.