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Abstract Decreased blood‐tissue oxygenation at high altitude (HA) increases mitochondrial oxidant production and reduces exercise capacity. 5‐Hydroxymethylfurfural (5‐HMF) is an antioxidant that increases hemoglobin's binding affinity for oxygen. For these reasons, we hypothesized that 5‐HMF would improve muscle performance in rats exposed to a simulated HA of ~5500 m. A secondary objective was to measure mitochondrial activity and dynamic regulation of fission and fusion because they are linked processes impacted by HA. Fisher 344 rats received 5‐HMF (40 mg/kg/day) or vehicle during exposure to sea level or HA for 72 h. Right ankle plantarflexor muscle function was measured pre‐ and post‐exposure. Post‐exposure measurements included arterial blood gas and complete blood count, flexor digitorum brevis myofiber superoxide production and mitochondrial membrane potential (ΔΨm), and mitochondrial dynamic regulation in the soleus muscle. HA reduced blood oxygenation, increased superoxide levels and lowered ΔΨm, responses that were accompanied by decreased peak isometric torque and force production at frequencies >75 Hz. 5‐HMF increased isometric force production and lowered oxidant production at sea level. In HA exposed animals, 5‐HMF prevented a decline in isometric force production at 75–125 Hz, prevented an increase in superoxide levels, further decreased ΔΨm, and increased mitochondrial fusion 2 protein expression. These results suggest that 5‐HMF may prevent a decrease in hypoxic force production during submaximal isometric contractions by an antioxidant mechanism.