When the COVID-19 pandemic began, U.S. college students reported increased anxiety and depression. This study examines mental health among U.S college students during the subsequent 2020–2021 academic year by surveying students at the end of the fall 2020 and the spring 2021 semesters. Our data provide cross-sectional snapshots and longitudinal changes. Both surveys included the PSS, GAD-7, PHQ-8, questions about students’ academic experiences and sense of belonging in online, in-person, and hybrid classes, and additional questions regarding behaviors, living circumstances, and demographics. The spring 2021 study included a larger, stratified sample of eight demographic groups, and we added scales to examine relationships between mental health and students’ perceptions of their universities’ COVID-19 policies. Our results show higher-than-normal frequencies of mental health struggles throughout the 2020–2021 academic year, and these were substantially higher for female college students, but by spring 2021, the levels did not vary substantially by race/ethnicity, living circumstances, vaccination status, or perceptions of university COVID-19 policies. Mental health struggles inversely correlated with scales of academic and non-academic experiences, but the struggles positively correlated with time on social media. In both semesters, students reported more positive experiences with in-person classes, though all class types were rated higher in the spring semester, indicating improvements in college students’ course experiences as the pandemic continued. Furthermore, our longitudinal data indicate the persistence of mental health struggles across semesters. Overall, these studies show factors that contributed to mental health challenges among college students as the pandemic continued.