Background Health workers (HWs) faced substantial risks during the COVID-19 pandemic. However evidence comparing their in-hospital mortality with that of non-health workers (non-HWs) in South Africa remains limited. This study compares in-hospital COVID-19 mortality and associated factors between hospitalized HW and non-HW groups from 2020 to 2022.Methods Cross-sectional analysis of national COVID-19 hospitalization data from 408 public and 262 private hospitals in South Africa was conducted. Our dataset included individuals aged 20–69 years with confirmed SARS-CoV-2 infection admitted between March 2020 and October 2022. Mortality outcomes were analysed using descriptive statistics, chi-square tests, and logistic regression to identify demographic, clinical, and contextual factors associated with death due to SARS-COV-2 infection.Results Overall in-hospital mortality was lower among HWs than non-HWs (16.3% vs 21.7%, p < 0.001). For both groups, older age, admission to intensive care, and treatment in public sector hospitals were associated with increased mortality. Among HWs, the strongest comorbidity predictors of death were chronic renal failure (aOR = 3.43), malignancy (aOR = 3.25), and active tuberculosis (aOR = 2.34). In non-HWs, mortality risk was more broadly elevated across active tuberculosis (aOR = 1.67), malignancy (aOR = 1.64), chronic renal failure (aOR = 1.60), diabetes (aOR = 1.41), HIV (aOR = 1.35), obesity (aOR = 1.18), and cardiac disease (aOR = 1.16). COVID-19 vaccination was strongly protective in both groups (aOR; HWs = 0.5 vs non-HWs = 0.72), with significantly reduced odds of death compared to unvaccinated individuals.Conclusion HWs had lower in-hospital mortality than non-HWs, likely reflecting earlier access to vaccination, better healthcare access, and proactive disease management. However, HWs with serious comorbidities—particularly renal failure, malignancy, and tuberculosis—remained at high risk. These findings highlight the importance of sustained vaccination, targeted protection for high-risk groups, and addressing systemic inequities in healthcare delivery to strengthen resilience for future pandemics.