Sepsis is the most common cause of death for patients in intensive care worldwide due to a dysregulated host response to infection. Here, we investigate the role of sequestosome-1 (SQSTM1/p62), an autophagy receptor that functions as a regulator of innate immunity, in sepsis. We find that lipopolysaccharide elicits gasdermin D-dependent pyroptosis to enable passive SQSTM1 release from macrophages and monocytes, whereas transmembrane protein 173-dependent TANK-binding kinase 1 activation results in the phosphorylation of SQSTM1 at Ser403 and subsequent SQSTM1 secretion from macrophages and monocytes. Moreover, extracellular SQSTM1 binds to insulin receptor, which in turn activates a nuclear factor kappa B-dependent metabolic pathway, leading to aerobic glycolysis and polarization of macrophages. Intraperitoneal injection of anti-SQSTM1-neutralizing monoclonal antibodies or conditional depletion of Insr in myeloid cells using the Cre–loxP system protects mice from lethal sepsis (caecal ligation and puncture or infection by Escherichia coli or Streptococcus pneumoniae) and endotoxaemia. We also report that circulating SQSTM1 and the messenger RNA expression levels of SQSTM1 and INSR in peripheral blood mononuclear cells are related to the severity of sepsis in 40 patients. Thus, extracellular SQSTM1 has a pathological role in sepsis and could be targeted to develop therapies for sepsis.