Punicalagin, a polyphenolic compound extracted from pomegranate peel, has received increasing attention in recent years due to its antibacterial and antiviral properties. Punicalagin is capable of inhibiting bacterial growth at sub-inhibitory concentrations by affecting cell membrane formation, disrupting membrane integrity, altering cell permeability, affecting efflux pumps, interfering with quorum sensing and influencing virulence factors. Additionally, punicalagin inhibits viruses by modulating enzyme activity, interacting with viral surface proteins, affecting gene expression, blocking viral attachment, disrupting virus receptor interaction and inhibiting viral replication. Notably, it exerts synergistic effects on bacterial infections in combination with certain antibiotics, such as oxacillin, particularly against methicillin-resistant Staphylococcus aureus. However, the wide variation in the minimum inhibitory concentrations (MICs) of punicalagin against various bacterial strains, in addition to the lack of safety, toxicity, or side-effect profile data, underscores the need for additional studies. The present review discusses the advances in the antibacterial and antiviral activities of punicalagin, with in-depth analyses of its mechanisms of action and potential applications in combating microbial infections. Future research is required to focus on addressing the variability in reported MICs, optimizing their bioavailability and conducting preclinical studies to provide a new paradigm for the antimicrobial applications of natural polyphenols.