Protease is the enzyme accountable for the breakdown of proteins i.e., proteolysis. Proteases are reportedly involved in the events of growth, development, progression and metastasis of cancers. If any agent could inhibit/retard the protease enzyme, i.e., protease inhibitor, it would arrest the cancer; thus indicating the significance of exploring protease inhibitors for latest anti-malignant drug discovery. Higher plants are the rich sources of different protease inhibitors that are effective against several types of malignancies both at preclinical and clinical stages. Natural protease inhibitors of herbal origin have both cancer chemopreventive and chemotherapeutic properties together with inhibitory activity against different types of pertinent proteases. Clinically, these herbal agents are found to be safe unlike the synthetic antineoplastic agents. Further studies in this direction are necessary in pursuit of newer generation drugs without adverse reactions for the prevention and treatment of malignancies.