It is commonly thought that disruption of the circadian clock increases the cancer incidence in humans and mice. However, it was found that disruption of the clock by the Cryptochrome (Cry) mutation in mice did not increase cancer rate in the mutant mice even after exposing the animals to ionizing radiation. Therefore, in this study we tested the effect of the Cry mutation on carcinogenesis in a mouse strain prone to cancer because of a p53 mutation, with the expectation that clock disruption in this sensitized background would further increase cancer risk. Paradoxically, we find that the Cry mutation protects p53 mutant mice from the early onset of cancer and extends their median lifespan approximately 50%, in part by sensitizing p53 mutant cells to apoptosis in response to genotoxic stress. These results suggest alternative therapeutic approaches in management of cancers associated with a p53 mutation.