Background Differentiated service delivery (DSD) models in resource-limited settings have reduced strain on health services and improved client experience, retention and viral suppression, but little is known about the impact of HIV DSD models on quality of life (QoL), which is essential for optimizing person-centered care. This study assessed the impact of DSD models on QoL, loss to follow-up (LTFU), and mortality among persons living with HIV (PLHIV) on ART over time at a large urban HIV clinic in Uganda.Methods We analyzed records of 1,000 PLHIV who had been on ART for 10 years and followed up for eight years, starting in 2014 or 2015 at the Infectious Diseases Institute clinic in Kampala, Uganda. The primary outcome, QoL, was assessed using an adapted Medical Outcomes Study (MOS-HIV) tool. Secondary outcomes included sustained viral suppression (< 200 copies/mL), all-cause mortality, and loss to follow-up or LTFU (missing clinic visits for ≥ 3 months). Outcomes were compared across three DSD models—fast-track drug refill (FTDR), facility-based groups (FBG), and a composite model combining FTDR and FBG against the facility-based individual management (FBIM), the standard of care (SOC). Inverse probability treatment weighting was used to achieve comparability in measured covariates across the DSD models followed by mixed effects modeling. Robustness of results was checked using G-computation analysis.Results Of 1,000 records for PLHIV, 980 were analyzed. 62% were female and 95% virally suppressed at baseline. After eight years of follow-up, participants on DSD models had higher QoL (90.4% vs 89.1%; weighted mean ratio 3.66, 95% CI 2.10–6.37, p-value < 0.001), better sustained viral suppression, lower mortality, and reduced LTFU rates compared to SOC.Conclusion These findings support the broader adoption of DSD models in delivering ART across HIV programs to enhance the QoL and clinical outcomes among PLHIV.