AbstractThe use of antiviral COVID-19 medications can successfully inhibit SARS-CoV-2 replication and prevent disease progression to a more severe form. However, the timing of antiviral treatment plays a crucial role in this regard. Oral antiviral drugs provide an opportunity to manage SARS-CoV-2 infection without a need for hospital admission, easing the general burden that COVID-19 can have on the healthcare system. This review paper (i) presents the potential pharmaceutical antiviral targets, including various host-based targets and viral-based targets, (ii) characterizes the first-generation anti-SARS-CoV-2 oral drugs (nirmatrelvir/ritonavir and molnupiravir), (iii) summarizes the clinical progress of other oral antivirals for use in COVID-19, (iv) discusses ethical issues in such clinical trials and (v) presents challenges associated with the use of oral antivirals in clinical practice. Oral COVID-19 antivirals represent a part of the strategy to adapt to long-term co-existence with SARS-CoV-2 in a manner that prevents healthcare from being overwhelmed. It is pivotal to ensure equal and fair global access to the currently available oral antivirals and those authorized in the future.