This study explored substance use trajectories and associations with mental health among an ethnically/racially diverse college student sample before and during the COVID-19 pandemic. We combined repeated cross-sections and panel data from a total of 3,247 college students assessed with an online survey in 2018, 2019, and in three waves in 2020. We estimated trends in substance use and their relation to mental health over the survey waves using generalized estimating equations (GEE). Our results revealed notable associations between 30-day substance use patterns, time of assessment, and psychological well-being. These findings suggest a complex interplay between access to substances, context of substance use, and mental health. We discuss several initiatives that have been launched in response to the results of this ongoing study. Such initiatives may serve as examples for expanding similar efforts to other commuter colleges to prevent further increases in mental health problems and risky substance use.