Objective To explore whether voluntary wheel running affects liver oxidative stress by regulating Nrf2/HO-1 pathway, thereby alleviating HFFC diet-related lipid deposition in liver. Methods 8-week-old C57BL/6J mice were randomly divided into normal diet group (NC group, n=10) and high fat, fructose and cholesterol diet group (HFFC group, n=20) after a week of adaptive feeding. Ten weeks of feeding later, mice in HFFC group were divided into quiet group (HFFC group, n=10) and HFFC combined with exercise intervention group (HFFC+EX group, n=10). HFFC+EX group mice were caged with voluntary running wheels for free movement, and the number of running wheels was recorded every day for 8 weeks. After the last intervention, the mice were sacrificed by fasting for 12 hours at an interval of 24 hours, and the blood and liver were taken for detection. Results (1) The body weight, liver weight and liver index of mice induced by HFFC diet were significantly higher than those of NC group, and significantly decreased after exercise intervention (P<0.05). (2) Compared with NC group, HDL-C and LDL-C in HFFC group were significantly increased, and LDL-C level was significantly decreased after 8 weeks of exercise intervention (P<0.05). (3) The liver fat drop area and liver TG content in HFFC group were significantly higher than those in NC group, while those in HFFC+EX group were significantly decreased (P<0.05). (4) Compared with NC group, the content of oxidase MDA and the expression level of HO-1 in HFFC group were significantly increased, and the nuclear translocation and gene expression of Nrf2 were significantly decreased. After exercise intervention, the activities of SOD and T-AOC were significantly decreased, and the nuclear translocation and gene expression of Nrf2, the expression levels of HO-1 and SOD-1 were significantly increased (P<0.05). (5) The number of hepatocyte apoptosis and CHOP expression in HFFC diet group were significantly higher than those in NC group, while the number of hepatocyte apoptosis, CHOP and Bax/Bcl-2 expression in exercise group were significantly lower than those in NC group (P<0.05). Conclusions Voluntary wheel running can alleviate liver lipid deposition induced by HFFC diet by regulating Nrf2/HO-1 pathway, thereby alleviating oxidative stress and reducing apoptosis in liver cells.