Assessing and promoting physical activity and health-related quality of life (HRQOL) have become major public health issues, but little is known regarding HRQOL and its relation with physical activity in adolescents. This study attempted to examine relationships among middle school students’ motivation, physical activity, and HRQOL by using the expectancy-value model as a theoretical framework. Participants were 282 middle school students who responded to a previously validated inventory assessing their motivation, physical activity, and HRQOL. Correlation analyses revealed that expectancy-related beliefs and task values were positively related to physical activity and HRQOL. Physical activity was positively associated with physical, emotional, and social functioning of HRQOL. Regression analyses showed a significant relationship between increasing expectancy-related beliefs and increasing degrees of HRQOL. This research line is promising in that it can provide useful information regarding the translation of theory to practice in influencing adolescents’ physical activity and HRQOL.