Chemokine receptor type 4 (CXCR4) is a G protein-coupled receptor that plays an essential role in immune system function and disease processes. Our study aims to conduct a comparative structural and phylogenetic analysis of the CXCR4 protein to gain insights into its role in emerging and re-emerging diseases that impact the health of mammals. In this study, we analyzed the evolution of CXCR4 genes across a wide range of mammalian species. The phylogenetic study showed species-specific evolutionary patterns. Our analysis revealed novel insights into the evolutionary history of CXCR4, including genetic changes that may have led to functional differences in the protein. This study revealed that the structural homologous human proteins and mammalian CXCR4 shared many characteristics. We also examined the three-dimensional structure of CXCR4 and its interactions with other molecules in the cell. Our findings provide new insights into the genomic landscape of CXCR4 in the context of emerging and re-emerging diseases, which could inform the development of more effective treatments or prevention strategies. Overall, our study sheds light on the vital role of CXCR4 in mammalian health and disease, highlighting its potential as a therapeutic target for various diseases impacting human and animal health. These findings provided insight into the study of human immunological disorders by indicating that Chemokines may have activities identical to or similar to those in humans and several mammalian species.