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Abstract Background Skeletal muscle atrophy is a common clinical manifestation of various neurotrauma and neurological diseases. In addition to the treatment of primary neuropathies, it is a clinical condition that should be investigated. FoxO3 activation is an indispensable mechanism in denervation‐induced muscle atrophy; however, upstream factors that control FoxO3 expression and activity have not been fully elucidated. N6‐methyladenosine (m6A) methylation is a novel mode of epitranscriptional gene regulation that affects several cellular processes. However, the biological significance of m6A modification in FoxO3‐dependent atrophy is unknown. Methods We performed gain‐of‐function and loss‐of‐function experiments and used denervation‐induced muscle atrophy mouse model to evaluate the effects of m6A modification on muscle mass control and FoxO3 activation. m6A‐sequencing and mass spectrometry analyses were used to establish whether histone deacetylase 4 (HDAC4) is a mediator of m6A demethylase ALKBH5 regulation of FoxO3. A series of cellular and molecular biological experiments (western blot, immunoprecipitation, half‐life assay, m6A‐MeRIP‐qPCR, and luciferase reporter assays among others) were performed to investigate regulatory relationships among ALKBH5, HDAC4, and FoxO3. Results In skeletal muscles, denervation was associated with a 20.7–31.9% decrease in m6A levels (P