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Cellular metabolism plays a major role in the regulation of inflammation. The inflammatory macrophages undergo a wide‐range of metabolic rewriting due to the production of significant amount of itaconate metabolite from cis‐aconitate in the tricarboxylic acid cycle. This itaconate molecule has been recently described as a promising immunoregulator. However, its function and mode of action on macrophages and tissue repair and regeneration are yet unclear. Herein, the itaconate‐derivative dimethyl itaconate (DMI) suppresses the IL‐23/IL‐17 inflammatory axis‐associated genes and promotes antioxidant nuclear factor erythroid 2‐related factor 2 target genes. The poly‐ε‐caprolactone (PCL)/DMI nanofibers implanted in mice initially maintain inflammation by suppressing anti‐inflammatory activity and particular inflammation, while at later stage promotes anti‐inflammatory activity for an appropriate tissue repair …