Stressful life events (SLEs) increase allostatic load and require adaptation. Experiencing SLEs has been associated with decreased health-related quality of life (HRQOL) among adolescents. This study examined racial/ethnic and developmental differences in the relationship between SLEs and HRQOL from preadolescence to mid adolescence. Data were from 4,824 participants in the Healthy Passages project, a population-based prospective longitudinal survey of fifth, seventh, and 10th grade adolescents in the U.S. HRQOL was measured with Pediatric Quality of Life Inventory and SLEs with items addressing family-related SLEs (e.g., the parent’s death, separation, and divorce; family member’s injury/illness; residential change; new child in the household). Adolescents, regardless of race/ethnicity, reported the highest SLEs and the lowest HRQOL in early adolescence. Analysis of an autoregressive model with cross-lagged effects showed that the concurrent relationships between SLEs and HRQOL were significantly negative across preadolescence, early adolescence, and mid adolescence in African-American, Latinx, and white groups. Furthermore, adolescents had a negative cross-lagged association from SLEs in early adolescence to HRQOL in preadolescence, but this was not the case among the other racial/ethnic groups. Because the negative relationship between family-related SLEs and HRQOL persisted throughout stages of adolescent development, health services targeting adolescents should provide comprehensive family-centered care to alleviate the impact of family-related life stress. Relationships between family life stress and HRQOL varied by racial/ethnic groups, which should be considered by health professionals, teachers, and parents, and in prevention efforts. Latinx adolescents may be particularly vulnerable to time-lagged effects of such family-related stress.