Background: Young adulthood is a period of increasing independence for the 40% of young adults enrolled in U.S. colleges. Previous research indicates differences in how students’ health behaviors develop and vary by gender, race, ethnicity, and socioeconomic status. George Mason University is a state institution that enrolls a highly diverse student population, making it an ideal setting to launch a longitudinal cohort study using multiple research methods to evaluate the effects of health behaviors on physical and psychological functioning, especially during the COVID-19 pandemic. Results: Mason: Health Starts Here was developed as a longitudinal cohort study of successive waves of first year students that aims to improve understanding of the natural history and determinants of young adults’ physical health, mental health, and their role in college completion. The study recruits first year students who are 18 to 24 years old and able to read and understand English. All incoming first year students are recruited through various methods to participate in a longitudinal cohort for 4 years. Data collection occurs in fall and spring semesters, with online surveys conducted in both semesters and in-person clinic visits conducted in the fall. Students receive physical examinations during clinic visits and provide biospecimens (blood and saliva). Conclusions: The study will produce new knowledge to help understand the development of health-related behaviors during young adulthood. A long-term goal of the cohort study is to support the design of effective, low-cost interventions to encourage young adults’ consistent performance of healthful behaviors, improve their mental health, and improve academic performance.