The evolving epidemiology of COVID-19, driven by successive SARS-CoV-2 variants of concern (VOCs), has prompted ongoing evaluation of their impact on disease severity in children. In low- and middle-income countries (LMICs), children experience a higher burden of severe respiratory illness and pneumonia-related mortality due to factors such as malnutrition, incomplete immunisation, HIV exposure or infection, tuberculosis, and disparities in access to healthcare services. Hospital-based paediatric studies from LMICs are therefore needed to understand how the epidemiology and severity of COVID-19 have changed across pandemic waves. This study examined 354 hospitalised children with SARS-CoV-2 infection during the ancestral, pre-Omicron (Beta and Delta), and Omicron waves at Tygerberg Hospital in Cape Town, South Africa. We analysed data collected over an extended period, from March 2020 to June 2022. Statistical analyses were used to describe clinical characteristics across variant periods, and multivariable logistic regression models were applied to evaluate associations between potential risk factors and disease severity. Paediatric COVID-19 severity varied across VOC periods, with the highest burden observed during the pre-Omicron (Beta and Delta) waves. In multivariable analyses, younger age and circulating variants were associated with disease severity; CRP levels emerged as a marker associated with more severe illness, and corticosteroid treatment, while also associated with disease severity, reflects clinical response to more severe cases. These findings contribute to a better understanding of the epidemiology and clinical impact of COVID-19 in children and highlight the importance of context-specific surveillance and treatment strategies in resource-limited settings.