The outbreak of coronavirus in the year 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prompted widespread illness, death, and extended economic devastation worldwide. In response, numerous countries, including Botswana and South Africa, instituted various clinical public health (CPH) strategies to mitigate and control the disease. However, the emergence of variants of concern (VOC), vaccine hesitancy, morbidity, inadequate and inequitable vaccine supply, and ineffective vaccine roll-out strategies caused continuous disruption of essential services. Based on Botswana and South Africa hospitalization and mortality data, we studied the impact of age and gender on disease severity. Comparative analysis was performed between the two countries to establish a vaccination strategy that could complement the existing CPH strategies. To optimize the vaccination roll-out strategy, artificial intelligence was used to identify the population groups in need of insucient vaccines. We found that COVID-19 was associated with several comorbidities. However, hypertension and diabetes were more severe and common in both countries. The elderly population aged ≥ 60 years had 70% of major COVID-19 comorbidities; thus, they should be prioritized for vaccination. Moreover, we found that the Botswana and South Africa populations had similar COVID-19 mortality rates. Hence, our findings should be extended to the rest of Southern African countries since the population in this region have similar demographic and disease characteristics.