ABSTRACT This study presents an analysis and comparison of the health security practices (HSP) of 47 African countries based on 2019 and 2021 data. Its objective is to assess, rank, and cluster the countries based on their HSP performance and progress over this period. A comprehensive Entropy-TOPSIS-K-means-based evaluation system was constructed for this purpose. Initially, the entropy method was utilised to analyze and compare investment priorities. Subsequently, the Entropy-TOPSIS was used to evaluate and compare the level of health security (HS) performance and the degree of improvements made by countries over the study period. Finally, the K-means cluster analysis method was applied to classify countries based on their comprehensive evaluation scores. Among the six identified criteria, prevention, detection, reporting, and health system practices were deemed crucial for HS decision-making in both cases. The study revealed significant differences in HSP levels and changes in countries’ improvement levels between their practices in 2019 and 2021. The study classifies the security levels of African countries into five clusters and provides a detailed analysis, implications, and recommendations to aid decision-makers in enhancing HS outcomes. Its results offer empirical evidence to support planning, resource allocation, and reallocation for strengthening HSP in the region.