Schizophrenia (SCZ) is a complex disorder characterized by acute symptom exacerbations. Amisulpride, an antipsychotic, has shown effects beyond its primary neurochemical actions, suggesting an influence on the gut microbiome, cytokine modulation, and short-chain fatty acid (SCFA) metabolism. This study aims to investigate these broader effects by examining changes in serum SCFA levels and gene expression profiles in peripheral blood mononuclear cells (PBMCs) following amisulpride treatment. Patients with SCZ undergoing a four-week amisulpride regimen were enrolled. Serum SCFA levels were quantified by gas chromatography, and gene expression profiling was performed in PBMCs using real-time quantitative polymerase chain reaction to assess treatment-associated changes. Results revealed that treatment with amisulpride resulted in a significant increase in serum acetate levels. Gene expression analysis revealed upregulation of G-protein coupled receptor 109a (GPR109a), histone deacetylase 1 (HDAC1), G-protein coupled receptor 43 (GPR43), Toll-like receptor 2 (TLR2), soluble CD14 (sCD14), and N-methyl-d-aspartate receptor (NMDAR), while Toll-like receptor 4 (TLR4) and pregnane X receptor (PXR) were downregulated. These findings suggest that amisulpride may modulate acetate metabolism and immune signaling pathways in SCZ, potentially contributing to anti-inflammatory effects and neuroimmune regulation. The observed increase in acetate, a key microbial metabolite, and the altered expression of immune-related genes suggest a possible link between metabolic shifts and immunomodulatory responses in SCZ pathophysiology. However, direct evidence linking these changes to gut-brain axis mechanisms remains insufficient. Further research is needed to elucidate the therapeutic implications of these metabolic and immunological alterations and their potential role in symptom modulation.