Purpose: The 2 × 2 achievement goal model, including the mastery-approach, mastery-avoidance, performance-approach, and performance-avoidance goal orientations, has recently been used to explain motivational outcomes in physical activity. This study attempted to examine the relationships among 2 × 2 achievement goal orientations, physical activity, and health-related quality of life (HRQOL) in college students. Method: Participants were 325 students (130 men and 195 women; M[subscript age] = 21.4 years) enrolled in physical activity classes at a Southern university. They completed surveys validated in previous research assessing achievement goal orientations, physical activity, and HRQOL. Results: Path analyses revealed a good fit between the model and data (root mean square error of approximation = 0.06; Comparative Fit Index = 0.99; Bentler-Bonett Nonnormed Fit Index = 0.98; Incremental Fit Index = 0.99), but the model explained small variances in the current study. Mastery-approach and performance-approach goal orientations only had low or no relationships with physical activity. Mastery-approach goal orientation and physical activity also had low positive relationships with HRQOL, but mastery-avoidance and performance-avoidance goal orientations had low negative relationships with HRQOL. The hypothesized mediational role of physical activity in the relationship between mastery-approach and performance-approach goal orientations and HRQOL was not supported in this study. Conclusions: Although the data fit the proposed model well, only small variance was explained by the model. The relationship between physical activity and HRQOL of the college students and other related correlates should be further studied.