Objectives: Identification of health-related risk behaviors associated with well-being in college students is essential to guide the development of health promotion strategies for this population. The purposes were to evaluate well-being among undergraduate students and to identify health-related risk behaviors that predict well-being in this population. Methods: A cross-sectional Web-based survey of undergraduate students was conducted at a metropolitan university in the Southeast United States. A total of 568 students responded (response rate 14.2%). Data were collected on health-related risk behaviors using the National College Health Assessment II. Results: Controlling demographic characteristics, the best predictive model included physical activity, current tobacco user, depression, ever received mental health services, and sleep quality, which was the strongest predictor (ß = 0.45, p < 0.001). This model explained 35% of the variance in well-being. Conclusions: Interventions that promote sleep quality among college students may be most beneficial in improving well-being.