This study gathered preliminary data on the impact of the U.S. response to the COVID-19 pandemic on the substance use, sexual behavior, and general well-being of U.S. college students. Participants from colleges across the U.S. (N = 212; 50.5% female; M age = 22.09) completed an online survey between May 20th and July 5th, 2020 about COVID-19-related behavior change. Most students reported a decrease in quality of life (71.7%), an increase in levels of anxiety (63.7%), and problems with basic resource needs (53.8%). Reports of alcohol consumption increased for 26.9% of students and 15.1% reported an increase in cannabis use. Most students (57.5%) reported a decrease in sexual activity, yet access to, and use of, condoms generally remained unchanged. As universities resume residential instruction, existing prevention and intervention services will need to be adapted to address the mental and behavioral health needs of college students during the era of COVID-19.