The Sinopharm COVID-19 vaccine was widely deployed in Pakistan to curb SARS-CoV-2 infections. Real-world post-pandemic evidence on its effectiveness and safety across diverse populations remains limited. This prospective observational study evaluated vaccine effectiveness (VE) and safety in 2,400 individuals from three cohorts: general adults (n=1,200), high-risk adults with comorbidities (n=800), and healthcare/frontline workers (n=400). Participants were followed for 12 months post-vaccination. Primary outcomes included incidence of laboratory-confirmed COVID-19 and hospitalization. Secondary outcomes were adverse events following immunization (AEFI). VE against symptomatic COVID-19 was 76.3% (95% CI: 72.1–80.2%) in the general adult cohort, 68.5% (95% CI: 63.0–73.2%) in high-risk adults, and 81.9% (95% CI: 76.0–86.3%) among healthcare workers. Hospitalization rates were significantly lower in vaccinated participants compared to unvaccinated controls (1.7% vs 7.9%, p60 years) and individuals with multiple comorbidities. These findings indicate that the Sinopharm vaccine provides substantial protection against COVID-19 and demonstrates an excellent safety profile in real-world Pakistani populations. Continued monitoring is essential to evaluate durability of protection and effectiveness against emerging variants.