<p>This study develops a deterministic model to analyze the transmission dynamics of COVID-19, with a specific focus on comparing the Omicron and Delta variants in Nigeria. A key innovation of the model lies in the incorporation of prophylactic interventions, offering valuable insights for informing public health strategies. The analysis shows that the disease-free equilibrium is both locally and globally asymptotically stable when the basic reproduction number is less than one, indicating conditions necessary for effective disease containment. Sensitivity analysis is conducted to identify the most influential parameters affecting disease transmission and control, highlighting the critical role of detection rates, hospitalization, and prophylaxis. Numerical simulations, calibrated with real-world data from Nigerian health authorities, demonstrate that increasing detection rates, hospitalizing symptomatic individuals, and enhancing prophylaxis uptake substantially reduce infection levels. Furthermore, predictive tools developed through statistical and regression analysis reveal that the Omicron variant exhibited a higher transmission rate than the Delta variant, with a significant surge observed around day 20. The model also estimates that for every 1,000 confirmed cases, approximately 12 deaths may occur. These findings underscore the importance of data-driven interventions and improve forecasting accuracy for more effective pandemic management.</p><p><?noindent??><b>Clinical trial number</b> Not applicable.</p>