Punica granatum L (pomegranate) is one of the Mediterranean medicinal plants that has been used for generations in treating ulcers, diarrhea, and male infertility. Increasing evidence has revealed that pomegranate possesses myriads of pharmacological activities such as anti-diabetic, anti-tumor, anti-inflammatory, anti-malaria, anti-fibrotic, anti-fungal, anti-bacterial, and other effects. Consumption of pomegranate could be used to improve gut microbiota, and therefore prevent obesity and diabetes. The mechanisms of actions of pomegranate, mainly involve nuclear factor-erythroid factor 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-kB), and mitogen-activated protein kinase (MAPK) signaling pathways. In recent times, in silico molecular docking studies demonstrated that pomegranate extract and or its phytochemicals are potential inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) spike protein and angiotensin-converting enzyme 2 (ACE2) receptor contact. Also, some clinical trials have indicated that pomegranate can be consumed for alleviation of non-alcoholic fatty liver disease, metabolic syndrome, dental infections, and menopausal symptoms. To date, active compounds, viz. alkaloids, anthocyanidins, tannins, flavonoids, phenolics, proanthocyanidins, sterols, terpenes, terpenoids, xanthonoids, fatty acids, organic acids, lignans, saccharides, and vitamin C have been isolated from pomegranate. Therefore, the current review article aimed to gather and presents an update on the ethnomedicinal uses, pharmacological activities, phytochemistry, and molecular mechanisms of Punica granatum L. This knowledge is of paramount importance in the future in drug discovery for the development of novel natural drugs for the treatment of various ailments. © 2022 The Authors