The present study was aimed to evaluate the protective effects of Hydroethanolic Murraya koenigii leaves extract (HEMKLE) against DMBA/TPA-induced angiogenesis, hepatotoxicity and renal toxicity during skin carcinogenesis in mice. For the study, male LACA mice were divided into four groups: Group I (C), Group II (DMBA/TPA), Group III (HEMKLE), and Group IV (HEMKLE+DMBA/TPA). 7, 12-dimethylbenz(a) anthracene (DMBA), and 12-O-tetradecanoyl phorbol-13-acetate (TPA) were applied on the depilated skin of the mice to raise skin tumors in Group II and Group IV. The chemopreventive response of HEMKLE was evident by histoarchitectural and morphometric analysis of skin/tumors in Group IV (HEMKLE+DMBA/TPA). In addition, HEMKLE administration also decreased the mRNA and protein expression of HIF-1α, HMOX-1, VEGF, bFGF, and ANGPT-2 in Group IV (HEMKLE+DMBA/TPA) when compared to Group II (DMBA/TPA) that suggest its anti-angiogenic effect. Moreover, HEMKLE administration protected the liver and kidney tissues from damages incurred during skin carcinogenesis as evident through histological analysis, assessment of ROS and LPO levels, assessment of liver and kidney function markers (viz., SGOT, SGPT, D-bilirubin, T-bilirubin, ALP, urea, creatinine and BUN) and activities of the antioxidant enzymes in Group IV (HEMKLE +DMBA/TPA) when compared to Group II (DMBA/TPA). The outcome of the present study showed that HEMKLE administration markedly alleviated the angiogenesis and also showed the protective effects against damages incurred in liver and kidney tissues during skin carcinogenesis. However, further extensive studies are needed to explore the efficacy of HEMKLE on metastasis before going to human trials.