PURPOSE: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial cytoprotective protein that shields cells from electrophilic and oxidative stress. Mice lacking Nrf2 exhibit heightened susceptibility to myelosuppression due to impaired hematopoietic reconstitution. In this study, we examined the altered sensitivity to ionizing radiation (IR) and 7,12-dimethylbenz(a)anthracene (DMBA) in Nrf2(-/-) mice separately. MATERIALS AND METHODS: Irradiate Nrf2(-/-) or wild-type mice with a dose of 4 Gy to observe changes in body weight, survival rate, and blood routine at 12 months. DMBA was used to treat Nrf2(-/-) and wild-type mice, and the body weight and survival rate of the mice were measured. The changes of heme oxygenase-1(HO1) and NAD(P)H: quinone oxidoreductase 1(NQO1) in mice treated with IR or DMBA were detected by RT-qPCR and western blotting. RESULTS: Our results indicate that Nrf2 deficiency leads to more severe blood and immune system injury in mice exposed to IR or DMBA. Additionally, long-term monitoring revealed that Nrf2 deletion resulted in more severe myelosuppression, leukemia-like symptoms, and higher cancer rates. At the mRNA and protein levels, there was no significant increase in HO1 and NQO1 levels in the Nrf2(-/-) mice treated with IR or DMBA. These adverse effects might be attributed to the inhibited protein levels of HO1 and NQO1 and significant DNA damage in hematopoietic stem and progenitor cells (HSPCs). CONCLUSIONS: We demonstrate that the genetic deficiency of Nrf2 in mice leads to reduced antioxidant capacity and suppression of hematopoietic and immune system function, resulting in increased sensitivity to IR or DMBA.