Stroke is a major cerebrovascular condition triggered by sudden loss of cerebral blood flow, which leads to neurological impairment. Microglia are the main resident immune cells within the central nervous system. After ischemic injury, activated microglia release pro‑inflammatory cytokines that worsen ischemic brain damage. Blocking the release of these pro‑inflammatory mediators may therefore offer a way to reduce such injury. Golga4 localizes to the trans‑Golgi network (TGN). Earlier work has shown that suppressing Golga4 lowers TNF‑α secretion in macrophages. A 42‑amino‑acid domain at the C‑terminus of Golga4 is the minimal region needed to keep the protein anchored at the Golgi apparatus. Using qPCR, immunofluorescence staining, and flow cytometry, we found that Golga4 is strongly upregulated in microglia after ischemic stroke. We then knocked down microglial Golga4 in cell culture and in animal models, and showed that lower Golga4 levels in microglia suppress neuroinflammation and improve ischemic brain injury. In addition, we overexpressed this 42‑amino‑acid peptide in vitro. Our data show that this peptide disrupts the TGN localization of endogenous Golga4 and thereby reduces inflammatory cytokine release. In summary, our study identifies microglial Golga4 and its C‑terminal 42‑amino‑acid motif as a new regulator that controls inflammatory factor export from the trans‑Golgi network. Targeting Golga4 function in microglia, or disrupting the TGN localization dependent on this short peptide, can curb harmful neuroinflammation. These findings suggest Golga4 and its C‑terminal 42‑amino‑acid domain may serve as promising therapeutic targets for ischemic stroke.