Sedentary behavior may not differ between individuals meeting and not meeting physical activity guidelines (PAGs); however, sedentary behavior has been associated with lower levels of health-related quality of life (HRQoL). The purpose of this study was to investigate the influence of sedentary behavior on HRQoL across young adults in three physical activity engagement groups (i.e., did not meet aerobic or muscle-strengthening PAGs; met either aerobic PAGs or muscle-strengthening PAGs; and met both aerobic and muscle-strengthening PAGs) using moderation analyses. Participants were 427 young adults (<i>M</i><SUB>age</SUB> = 19.15 ± 0.77) from Southwestern U.S. public university. Participants completed an online survey assessing sedentary behavior, physical activity profile, and HRQOL. On average, participants who did not meet aerobic or muscle-strengthening PAGs reported the lowest physical and psychosocial HRQoL and highest screen-time sedentary behavior, while participants who met both aerobic and muscle-strengthening PAGs reported the highest physical and psychosocial HRQoL and lowest screen-time sedentary behavior. Moderation analyses indicated meeting both aerobic and muscle-strengthening PAGs significantly buffered the negative influence of screen-time sedentary behavior on physical HRQoL. Meanwhile, meeting only one of the PAGs (i.e., aerobic or muscle-strengthening) did not significantly buffer the negative influence of screen-time sedentary behavior on physical HRQoL. Considering the current trends of sedentary behavior, the current study provided support in promoting regularly engaging in both aerobic and muscle-strengthening activity. Moreover, it provided evidence supporting the position that interventions designed to improve HRQoL should include both aerobic and muscle-strengthening activity.