Objective: This study investigated the relationship between spiritual well-being (SWB) and various aspects of health-related quality of life (HRQL) of college students. Participants and Methods: Two hundred twenty-five participants were surveyed during October 2010 to assess SWB and HRQL using the Spiritual Well-Being Scale and questions from the Centers for Disease Control and Prevention's scale for HRQL, respectively. Hierarchical multiple linear regression analyses tested the relationship between SWB and multiple measures of HRQL while controlling for sex, age, and race. Results: Participants who reported higher SWB scores were more likely to participate in religious-type activities and report better HRQL compared with students who reported a moderate sense of SWB. Jointly, SWB and participation in religious activities explained 18% of the variance in HQRL in this sample. Conclusions: SWB made a significant contribution to HRQL in a sample of college students. Such a relationship should be considered by campus health program planners to improve the quality of life of young adults.