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The aim of this study is to evaluate the therapeutic efficacy of 2,4\u2010dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof\u2010of\u2010concept evidence of using DNP as a potential therapeutic drug for ALS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>hSOD1<jats:sup>G93A<\/jats:sup> mice were treated with 0.5\u20131.0\u2009mg\/kg DNP through daily oral gavage from presymptomatic stage or disease onset until 18\u2009weeks old. Longitudinal behavioral studies were performed weekly or biweekly from 6 to 18\u2009weeks old. In situ muscle contraction measurements in <jats:italic>extensor digitorum longus<\/jats:italic> muscles were conducted to evaluate the preservation of contractile force and motor unit numbers in hSOD1<jats:sup>G93A<\/jats:sup> mice following DNP treatment. Muscle innervation and inflammatory markers were assessed using immunostaining. Extent of protein oxidation and activation of Akt pathway were also examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DNP delayed disease onset; improved motor coordination and muscle performance in vivo; preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation; and reduced inflammation and protein oxidation at 18\u2009weeks old in hSOD1<jats:sup>G93A<\/jats:sup> mice. Strikingly, symptomatic hSOD1<jats:sup>G93A<\/jats:sup> mice exhibited a period of recovery in running ability at 20\u2009cm\/s several weeks after 2,4\u2010dinitrophenol treatment started at disease onset, offering the first observation in disease phenotype reversal using a small molecule.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our results strongly support that micro\u2010dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. 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