Objective: To examine the relationship between COVID-19-related distress and mental health among first-year college students. Participants: Data for this longitudinal study (n = 727) were collected before the school year (August 2019), end of fall semester (December 2019), and soon after the university suspended in-person instruction (April 2020). Methods: We used multivariable log-linear and logistic regressions to examine continuous and dichotomous outcomes on the 9-item Patient Health Questionnaire and the 7-item Generalized Anxiety Disorder scale. Results: The most consistent predictor of during-pandemic mental health was feeling extremely isolated (versus not at all), which was associated with increased symptom severity of depression (proportional change[95% CI] = 2.43[1.87, 3.15]) and anxiety (2.02[1.50, 2.73]) and greater odds of new moderate depression (OR[95% CI] = 14.83[3.00, 73.41]) and anxiety (24.74[2.91, 210.00]). Greater COVID-19-related concern was also related to increased mental health symptoms. Conclusions: Results highlight the need for mental health services during crises that lead to social isolation.