The scale-up of antiretroviral therapy (ART) has transformed the HIV epidemic in sub-Saharan Africa, yet longitudinal public health insights from national programmatic cohorts remain scarce. As global targets move toward epidemic control and elimination of virological failure, understanding how profiles and outcomes of people living with HIV (PLWH) evolve in real-world settings is essential. The AIDS Support Organisation (TASO), Uganda's largest HIV care provider, maintains one of the longest-running national registries of PLWH. We aimed to generate insights to inform targeted interventions, optimize programmatic responses and improve long-term care for PLWH in resource-constrained settings. We conducted a secondary analysis of routinely collected data within an open cohort of 54,348 PLWH enrolled at 11 TASO clinics between 2014-2024. Descriptive statistics summarized demographic, clinical, immunological, behavioral and socioeconomic characteristics at baseline and follow-up. At most recent recorded follow-up, 60.4% of PLWH were female with median age of 39 years (IQR 31-47); 55% aged 25-44 years. At ART initiation, non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens dominated (>90% through 2017), by 2024, > 99% of ART initiations were dolutegravir (DTG)- based, aligning with national policy. Immune recovery improved over study period; however, 12% still presented with CD4 < 200 cells/µL. Most PLWH initiated care in WHO stage I-II, and prevalence of advanced disease declined further at last record. Self-reported adherence exceeded 95%. Tuberculosis was the most frequent infectious comorbidity (5% prior history), whereas hypertension (3.9%) and diabetes (2.5%) were the leading non-communicable conditions. Socioeconomic vulnerability reported 57% with irregular income and 21% unemployed. Psychosocial stressors, including poverty and stigma, were common. Findings show progress alongside persistent gaps and structural barriers. They mandate earlier diagnosis, integrated tuberculosis and non-communicable disease management, strengthened socioeconomic support, and risk-stratified care using predictive modeling to reduce virological failure and drive Uganda toward 95-95-95 targets in resource-constrained settings.