Background: Doxorubicin (DOX) is associated with profound skeletal muscle dysfunction. Resistance training (RT) and creatine (Cr) monohydrate have been independently shown to protect against DOX-induced muscle dysfunction. However, no investigation has examined their combined effects on DOX-induced muscle dysfunction. Methods: Male Sprague-Dawley rats were randomly assigned to a RT or sedentary group. After 6 wk of training, the soleus (SOL) and extensor digitorum longus (EDL) were excised and placed in a tissue bath containing Krebs buffer (K) or a K containing Cr (25 mM) for 30 min. The buffers were refreshed with new K or K containing DOX (24 μM) and incubated for 30 min. Muscles were then subjected to maximal twitch and fatigue testing.Results: DOX-induced fatigue occurred at 40 s in the SOL and EDL. RT delayed DOX-induced fatigue by 20 s in the SOL and 10 s in the EDL. Cr treatment delayed the onset of DOX-induced fatigue by 10 s in the EDL. The combination of RT and Cr delayed DOX-induced fatigue by 50 s in the SOL and 20 s in the EDL.Conclusion: This study showed that a combined treatment with RT and Cr minimized DOX-induced fatigue in the SOL and EDL.