Health-related quality of life (HRQOL) is a comprehensive construct including physical and psychosocial health functioning. Despite significant health benefits of regular physical activity (PA), over 40% of female college students do not meet recommended PA guidelines to improve their health. This study investigated the influences of individual, social, and physical environmental factors on students’ PA and HRQOL. Participants were 235 female university students who completed validated surveys assessing their perceptions of PA, HRQOL, and social ecological factors. Three hierarchical regressions revealed individual and physical environmental factors as predictors of PA and HRQOL. These findings indicated health professionals need to consider students’ individual factors and physical environmental factors to promote female students’ PA and HRQOL.