The receptor for advanced glycation end products is associated with a series of physiological and pathological processes. Here, we studied the evolution of this multiligand receptor in primates and murine rodents. The evolutionary analyses reveal that adaptive selection had contributed to the variation at a number of amino acid sites in both taxa. Further, the major adaptively selected sites of both taxa are located on the extracellular ligand- and intracellular adaptor-binding regions and receptor oligomerization-related surfaces. The co-occurrence of adaptive evolution on the homologue domains suggests that they could play similar roles in these taxa. In terms of advantage fitness, the adaptive changes at these sites could contribute to host defence against the potential challenges towards these interactions and relevant signalling pathways, or the specificity of these essential points.