Retinal inflammatory microenvironment caused by microglia over-activation is deemed to be crucial pathological changes that lead to the massive death of retinal ganglion cells (RGCs) after traumatic optic neuropathy (TON), which then results in visual impairment and even blindness. Therefore, exploring effective targets to suppress microglia activation is a promising therapeutic strategy for TON. In the present work, we determined the roles of immune-responsive gene 1 (IRG1)/itaconate pathway on retinal microglia activation and neuroinflammation after TON, through endogenously manipulating Irg1 expression and exogenously supplementing itaconate derivatives, we evaluated its effects on RGCs survival, retinal structural damage and visual function after TON. Finally, we identified the downstream mechanism by which the Irg1/itaconate pathway regulates microglia through transcriptome analysis. We found that specifically overexpression of Irg1 in retinal microglia significantly inhibited microglia activation and alleviated neuroinflammation after TON, thereby promoting RGCs survival and improving visual function. While knockdown of Irg1 caused microglia over-activation and exacerbated neuroinflammation, thus aggravating RGCs damage and deteriorating visual function after TON. Further in vivo and in vitro experiments confirmed that itaconate derivatives significantly inhibited microglia activation and alleviated neuroinflammation, hence alleviated RGCs damage and visual impairment. Finally, transcriptome analysis indicated that complement and coagulation cascades pathway might be the crucial downstream mechanism of the Irg1/itaconate pathway. Our study identifies the Irg1/itaconate pathway as a prospective target for treating TON.