Background: With antiretroviral therapy, more people living with HIV (PLHIV) in resource-limited settings are virally suppressed and living longer. WHO recommends differentiated service delivery (DSD) as an alternative, less resource-demanding way of expanding HIV services access. Monitoring client’s health-related quality of life (HRQoL) is necessary to understand patients’ perceptions of treatment and services but is understudied in sub-Saharan Africa. We assessed HRQoL among ART clients in Tanzania accessing two service models. Methods: Cross-sectional survey from May–August 2019 among stable ART clients randomly sampled from clinics and clubs in the Shinyanga region providing DSD and clinic-based care. HRQoL data were collected using a validated HIV-specific instrument—Functional Assessment of HIV infection (FAHI), in addition to socio-demographic, HIV care, and service accessibility data. Descriptive analysis of HRQoL, logistic regression and a stepwise multiple linear regression were performed to examine HRQoL determinants. Results: 629 participants were enrolled, of which 40% accessed DSD. Similar HRQoL scores [mean (SD), p-value]; FAHI total [152.2 (22.2) vs 153.8 (20.6), p 0.687] were observed among DSD and clinic-based care participants. Accessibility factors contributed more to emotional wellbeing among DSD participants compared to the clinic-based care participants (53.4% vs 18.5%, p = < 0.001). Satisfactory (> 80% of maximum score) HRQoL scoring was associated with (OR [95% CI], p-value) being male (2.59 [1.36–4.92], p 0.004) among clinic participants and with urban residence (4.72 [1.70–13.1], p 0.001) among DSD participants. Conclusions: Similar HRQoL was observed in DSD and clinic-based care. Our research highlights focus areas to identify supporting interventions, ultimately optimizing HRQoL among PLHIV.