Cancer is the most commonly diagnosed type of disease and a major cause of death worldwide. Despite advancement in various treatment modules, there has been little improvement in survival rates and side effects associated with this disease. Medicinal plants or their bioactive compounds have been extensively studied for their anticancer potential. Novel drugs based on natural products are urgently needed to manage cancer through attenuation of different cell signaling pathways. In this regard, berberine is a bioactive alkaloid that is found in variety of plants, and an inverse association has been revealed between its consumption and cancer. Berberine exhibits an anticancer role through scavenging free radicals, induction of apoptosis, cell cycle arrest, inhibition of angiogenesis, inflammation, PI3K/AKT/mammalian target of rapamycin (mTOR), Wnt/β-catenin, and the MAPK/ERK signaling pathway. In addition, synergistic effects of berberine with anticancer drugs or natural compounds have been proven in several cancers. This review outlines the anticancer effects and mechanisms of action of berberine in different cancers through modulation of various cell signaling pathways. Moreover, the recent developments in the drug delivery systems and synergistic effect of berberine are explained.