Plants evolve to synthesize various natural metabolites to protect themselves against threats, such as insects, predators, microorganisms, and environmental conditions (such as temperature, pH, humidity, salt, and drought). Plant-derived toxic proteins are often secondary metabolites generated by plants. These proteins, including ribosome-inactivating proteins, lectins, protease inhibitors, α-amylase inhibitors, canatoxin-like proteins and ureases, arcelins, antimicrobial peptides, and pore-forming toxins, are found in different plant parts, such as the roots, tubers, stems, fruits, buds, and foliage. Several investigations have been conducted to explore the potential applications of these plant proteins by analyzing their toxic effects and modes of action. In biomedical applications, such as crop protection, drug development, cancer therapy, and genetic engineering, toxic plant proteins have been utilized as potentially useful instruments due to their biological activities. However, these noxious metabolites can be detrimental to human health and cause problems when consumed in high amounts. This review focuses on different plant toxic proteins, their biological activities, and their mechanisms of action. Furthermore, possible usage and removal strategies for these proteins are discussed.