The neem tree has attracted considerable research attention as a rich source of limonoids that have potent antioxidant and anti-cancer properties. The present study was designed to evaluate the chemopreventive potential of the neem limonoids azadirachtin and nimbolide based on in vitro antioxidant assays and in vivo inhibitory effects on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Both azadirachtin and nimbolide exhibited concentration-dependent anti-radical scavenging activity and reductive potential in the order: nimbolide > azadirachtin > ascorbate. Administration of both azadirachtin and nimbolide inhibited the development of DMBA-induced HBP carcinomas by influencing multiple mechanisms including prevention of procarcinogen activation and oxidative DNA damage, upregulation of antioxidant and carcinogen detoxification enzymes and inhibition of tumour invasion and angiogenesis. On a comparative basis, nimbolide was found to be a more potent antioxidant and chemopreventive agent and offers promise as a candidate agent in multitargeted prevention and treatment of cancer.