Background Gauteng province (GP) was one of the most affected provinces in the country during the first two pandemic waves in South Africa. We aimed to describe the characteristics of coronavirus disease 2019 (COVID-19) patients admitted in one of the largest quaternary hospitals in GP during the first two waves.Objectives Study objectives were to determine factors associated with hospital admission during the second wave and to describe factors associated with in-hospital COVID-19 mortality.Method Data from a national hospital-based surveillance system of COVID-19 hospitalisations were used. Multivariable logistic regression models were conducted to compare patients hospitalised during wave 1 and wave 2, and to determine factors associated with in-hospital mortality.Results The case fatality ratio was the highest (39.95%) during wave 2. Factors associated with hospitalisation included age groups 40–59 years (adjusted odds ratio aOR: 2.14, 95% confidence interval CI: 1.08–4.27), 60–79 years (aOR: 2.49, 95% CI: 1.23–5.02) and ≥ 80 years (aOR: 3.39, 95% CI: 1.35–8.49). Factors associated with in–hospital mortality included age groups 60–79 years (aOR: 2.55, 95% CI: 1.11–5.84) and ≥ 80 years (aOR: 5.66, 95% CI: 2.12–15.08); male sex (aOR: 1.56, 95% CI: 1.22–1.99); presence of an underlying comorbidity (aOR: 1.76, 95% CI: 1.37–2.26), as well as being admitted during post–wave 2 (aOR: 2.42, 95% CI: 1.33–4.42).Conclusion Compared to the recent omicron-driven pandemic waves characterised by lower admission rates and less disease severity among younger patients, COVID-19 in-hospital mortality during the earlier waves was associated with older age, being male and having an underlying comorbidity.Contribution This study showed how an active surveillance system can contribute towards identifying changes in disease trends.