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Diet-induced inflammation is one main factor contributing to muscle degeneration in fish. Due to their anti-inflammatory and antioxidant properties, polyphenols have recently received great attention as feed additives in aquaculture. We used a combined immunohistochemical, western blotting (WB) and proteomic approach to evaluate the hypothesis that a pro-inflammatory diet in zebrafish (Danio rerio) results in skeletal muscle inflammation and morphological degeneration, and that dietary polyphenols may prevent and/or revert such conditions. Experimental groups were fed with a supplement mixture of polyphenols (tannins from chestnut shell of Castanea sativa and apigenin from Verbascum macrurum) before (PVpreI), during (PVwithI) and after (PVpostI) the pro-inflammatory diet. Diet-induced inflammation was characterized by muscle fibers morphological degeneration, ample intercellular space, and increased immunoexpression of TNF-α, cyclooxygenase 2 (COX2), and caspase 3. Polyphenols supplementation prevented and/or partially counteracted muscle morphological alterations and decreased TNF-α, COX2, and caspase 3 immunoexpression. WB analysis showed changes of IκBα phosphorylation, desmin and titin in inflamed muscle, which were fully/partially reverted in PVpreI and PVwithI groups. Proteomic analysis showed quantitative variations in structural and tissue regeneration proteins and their regulators, components of the connective tissue layer, molecules involved in inflammation and defense, and metabolite transporters, aligning with the observed morphological and molecular changes and their recovery depending on polyphenols treatments. In conclusion, polyphenol pre-treatment appeared effective in counteracting skeletal muscle inflammation, followed for efficacy by co-treatment and post-treatment, which only partially reverted diet-induced inflammation effects. These results strongly support the use of dietary polyphenols supplementation to prevent and/or counteract diet-induced muscle inflammation preserving muscle integrity and fish health.