Despite research attention toward understanding relationships between psychological need satisfaction (PNS), moderate-to-vigorous-intensity physical activity (MVPA), and health-related quality of life (HRQoL), methodological limitations make it difficult to establish reciprocal and mediating effects. Reciprocal relationships between PNS and MVPA were examined over 4 years, and their effects on adolescents’ change in dimensions of HRQoL were examined. Self-reported data were collected from 932 adolescents (M_age = 10.9 years) every 4 months beginning in Grades 5/6. At the between-persons and within-person level, earlier PNS predicted later MVPA whereas earlier MVPA did not predict later PNS. Increases in MVPA were associated with greater change in physical (β_linear = .61, β_quadratic = .77, ps = .03) and school functioning (β_linear = .68, β_quadratic = .84, ps = .03) but no other dimensions of HRQoL (p > .05). Decreases in PNS were not associated with any of the dimensions of HRQoL. Fostering adolescents’ PNS could be a starting point to increase MVPA, which, in turn, may enhance select dimensions of HRQoL.