US service members injured in the recent conflicts in Iraq and Afghanistan were more likely to survive than those in previous conflicts because of advances in medicine and protective gear. However, there is limited research examining the long-term impact of injuries while deployed on physical and mental quality of life (QOL) among service members. We used data from two time-points with an average follow-up period of 4.27 years (SD = 2.13; n = 118,054) to prospectively examine the association between deployment and injury status with QOL. Data were derived from the Millennium Cohort Study surveys (2001 to 2016) and linked with the Department of Defense Trauma Registry (DoD-TR) among a cohort of US service members from all branches and components. The primary predictor (a combination of deployment and injury status) was comprised of the following four categories: 1) not deployed, 2) deployed and not injured, 3) deployed and non-battle injured, and 4) deployed and battle injured. Demographic, military, psychological and behavioral health, and life stress factors were adjusted for in multivariable models. Outcomes of interest were physical and mental QOL from the Short-Form Health Survey for Veterans (VR-36) measured at ~4 year follow-up. Between group comparisons indicated that those deployed and battle-injured had the greatest decline in both mental (-3.82) and physical (-10.13) QOL scores over time (p < .05). While deployment and injury status were associated with poorer mental and physical QOL in adjusted models; only the association between deployment and injury status with physical QOL was clinically meaningful (more than 2.5). In adjusted models, Time 1 mental and physical QOL explained most of the variance (23-25%) in Time 2 mental and physical health QOL as compared to other covariates (e.g., injury and deployment, and other sociodemographic factors increased variance by ~5%). Time 1 QOL was the most significant predictor of later QOL, but those injured while deployed experienced significant and meaningful decrements to long-term physical QOL. This suggests that prevention and rehabilitation interventions should focus on improving physical health among injured service members to avoid long-term adverse effects.