Prohibitins (PHBs) are members of a highly conserved family of proteins, including prohibitin1 and prohibitin2. These proteins are predominantly localized in mitochondria, the nucleus, and cell membranes, where they play critical roles in mitochondrial biogenesis, apoptosis, immune regulation, and other biological processes. Recent studies have demonstrated that both PHB1 and PHB2 can act as a complex or independently to participate in the pathogen infection process. This review focuses on the regulatory roles of PHB1 and PHB2 in viral, bacterial, parasitic and fungal infections, providing a theoretical basis and innovative perspectives for a comprehensive understanding of the roles and mechanisms of PHB1 and PHB2 in the regulation of microbial infections. Due to exerting multiple functions, PHB proteins have been recognized as a potential target for therapeutic interventions, with the expectation that targeting PHB proteins will provide new strategies for the treatment of infection-related diseases.