While the majority of COVID-19 cases in South Africa (SA) are mild, patients with severe COVID-19 requiring hospitalisation present with significant morbidity and mortality and place a substantial burden on healthcare services. Given the low vaccine uptake in SA and other low- and middle-income countries in sub-Saharan Africa, the high prevalence of comorbidities and limited healthcare system capacity, evidence-based interventions that reduce the risk of severe disease and death should be considered for implementation. Several antiviral classes have been newly developed or repurposed to treat COVID-19 early after infection to retard progression to severe disease and reduce the risk of death, particularly in the elderly and/or in patients with comorbidities. COVID-19 antivirals such as remdesivir, nirmatrelvir/ ritonavir and molnupiravir are safe and cost-effective and have received either full approval or emergency use authorisation from regulators. Using a proposed test-and-treat strategy, judicious use of antivirals could be impactful.