Chemo-radiotherapy is the gold standard for the non-surgical management of cancer disease. However, patient receiving chemo-radiotherapy may lead to the genotoxicity of bone marrow. Therefore, Ipomoea pes-caprae as a potential chemoprotectant was evaluated against chemo-radiotherapy induced genotoxicity in C57BL mice. The present investigation evaluated the protective effect of Ipomoea pes-caprae against chemo-radiotherapy induced genotoxicity in mouse bone-marrow cells during the treatment of Melanoma cancer (B16F10). Methanol extract of the plant was administered to mice (25 and 50 mg/kg b. wt.) with the treatment dose of chemotherapy (Dacarbazine 50 mg/kg b. wt.) and radiotherapy (8Gy in 4 fractions, 2Gy in every 10th day to the tumor only) over a treatment time of 40 days. Significant increase (p<0.001) in the chromosomal aberrations were found for the tumor control, radiation control and dacarbazine administered groups. Significant increase in frequency of micronucleated polychromatic erythrocytes (MNPCEs) and micronucleated normochromatic erythrocytes (MNNCEs) was observed (p<0.01) in the tumor control, radiation control and dacarbazine administered groups, whereas the ratio of polychromatic and normochromatic erythrocytes (PCEs/NCEs) was found to be decreased. Methanolic extract treated group has shown a statistically significant (p<0.01) reduction in the aberrant metaphase and number of chromosomal aberrations as compared to tumor radiation control. Aberrant metaphase and incidence of micronuclei formation was found to be decreased in the experimental groups administered with plant extracts. The results of the present study concluded that I. pes-caprae has potential chemo-protection against chemo-radiotherapy induced genotoxicity during treatment of melanoma cancer in mice, which support its candidature as a potential chemo-radioprotective agent for cancer patients undergoing chemoradiotherapy.