Sepsis is an intractable clinical syndrome characterised by organ dysfunction when the body over-responds to an infection. Sepsis has a high fatality rate and lacks effective treatment. Family with sequence similarity 96 member A (FAM96A) is an evolutionarily conserved protein with high expression in the immune system and is related to cytosolic iron-assembly and tumour suppression; however, research has been rarely conducted on its immune functions. Our study found that Fam96a mice significantly resisted lesions during sepsis simulated by caecal ligation and puncture (CLP) or endotoxicosis models. After a challenge with lipopolysaccharide (LPS) or infection, Fam96a mice exhibited less organ damage, longer survival, and better bacterial clearance with decreased levels of proinflammatory cytokines. While screening several subsets of immune cells, FAM96A-expressing macrophages as the key cell type inhibited sepsis development. In vivo macrophage depletion or adoptive transfer experiments abrogated significant differences in the survival of sepsis between Fam96a and wild-type mice. Result of the bone-marrow-derived macrophage (BMDM) polarisation experiment indicated that FAM96A deficiency promotes the transformation of uncommitted monocytes/macrophages (M0) into M2 macrophages secreting less proinflammatory cytokines. FAM96A may mediate an immunometabolism shift-from oxidative phosphorylation (OXPHOS) to glycolysis-in macrophages during sepsis, mirrored by reactive oxygen species (ROS) and glucose uptake. These data demonstrate that FAM96A regulates inflammatory response and provide a novel genomic insight for sepsis treatment.This article is protected by copyright. All rights reserved.