[Purpose]To determine whether voluntary exercise (wheel running) has the potential of relieving stress. [Methods]In this study, restraint stress with or without voluntary wheel running was performed for mice housed in individual cages. A total of 21 ICR male mice were assigned into control (CON), restraint stress with voluntary exercise (RSVE), or restraint stress (RS) without voluntary exercise groups (n = 7 each). [Results]No significant difference in body weight increase was found among the three groups, although CON and RS groups had a tendency of having smaller body weight increase compared to the RSVE group. No significant difference in the expression level of liver heat shock protein 70, Bcl-2, or p53 was found among the three groups. However, caspase-3 protein level in RS group was significantly higher than that in the other two groups. Blood cortisol concentration in RS was higher (p < 0.05) than that in RSVE or CON group. It was the lowest (p < 0.05) in the RSVE group. [Conclusion]Our findings suggest that apoptosis caused by chronic restraint stress might be suppressed by voluntary exercise in mice.