Objective To construct type 2 diabetes mellitus (T2DM) models using wild-type (WT) mice and nuclear factor erythroid derived 2-like 2 (Nrf2) knockout (Nrf2KO) mice, and to explore the effect and mechanism of Nrf2 gene on bladder dysfunction in T2DM mice. Methods T2DM mouse model was constructed using male Nrf2KO mice and male WT mice in the same age, and the mice were randomly divided into Nrf2KO+T2DM group, Nrf2KO mouse control group (Nrf2KO group), T2DM modeling group (T2DM group), and WT mouse control group (WT group), with 10 mice in each group. The physiological signs and 24-h water intake and urine output of mice in each group were analyzed. The bladder tissue samples of mice were collected for histopathological analysis, and the expression of Nrf2 signaling pathway related proteins was analyzed by immunohistochemical staining and Western blotting. Results The body weight, bladder mass, blood glucose, glycosylated hemoglobin, and 24-h water intake and urine output of mice in the T2DM group were significantly higher than those in the WT group (all P<0.05), indicating that the T2DM mouse model was successfully established. The expression levels of nuclear Nrf2 and total Nrf2 proteins in the bladder tissues of mice in the T2DM group were significantly lower than those in the WT group (all P<0.05). The expression of apoptosis related molecules caspase 3 and oxidative stress-related products such as advanced glycation end products, malondialdehyde, and reactive oxygen species in bladder tissues of the Nrf2KO+T2DM group was significantly higher than that in the WT, Nrf2KO and T2DM groups (all P<0.05); the expression of antioxidant stress molecules reduced coenzyme/quinone oxidoreductase 1 and heme oxygenase 1 was significantly lower than that in the WT, Nrf2KO and T2DM groups (all P<0.05); the expression of nerve growth factor was significantly lower than that in the WT, Nrf2KO and T2DM groups (all P<0.05); however, the expression of the pro-form of nerve growth factor was significantly higher than that in the WT, Nrf2KO and T2DM groups (all P<0.05). Conclusion The inhibition of Nrf2 pathway leads to imbalance of oxidative stress regulation, bladder-related neuropathies and up-regulated expression of apoptosis pathway related proteins, and it may be an important mechanism of bladder dysfunction in T2DM mice.