Abstract: Background and Objective: Diabetes plays a vital role in the pathological process of muscular atrophy. Apocynin (APO) was proved to possess multiple biological effects in diabetes. However, its improvement in diabetic muscular atrophy has not been reported. Hence, the current article investigates the improvement of APO on diabetic muscular atrophy and its underlying mechanism. Materials and Methods: Haematoxylin and Eosin (HE) staining was utilized to observe gastrocnemius histopathology. Muscle force was tested according to the grip strength meter. The levels of ALT, AST, CK, LDH, T-AOC and MDA were measured by spectrophotometer. TNF-α and IL-6 levels were analyzed by ELISA kits. The expressions of Atrogin-1, MuRF-1, CHOP, GRP-78, BAX and BCL-2 were detected by Western blot. Results: Data demonstrated that APO markedly improved diabetic muscular atrophy, as represented by enhancing myofiber size and weight of gastrocnemius and promoting grip strength. In serum, APO markedly promoted T-AOC levels, while restrained ALT, AST, CK, LDH, MDA, TNF-α and IL-6 levels. In gastrocnemius, diabetes markedly increased the expressions of Atrogin-1, MuRF-1, CHOP, GRP-78 and BAX and reduced BCL-2 expression. However, treatment with APO reversed these changes. Conclusion: Results revealed that APO could attenuate Endoplasmic Reticulum (ER) and apoptosis in the gastrocnemius of diabetic mice and could be used as a novel therapeutic in the prevention and treatment of muscular atrophy.