G protein-coupled receptor 174 (GPR174) is mainly expressed in thymus, spleen, lymph nodes, and leukocytes, and genetic variation in GPR174 is associated with susceptibility to autoimmune diseases, indicating that GPR174 is involved in the immune response. However, the function of GPR174 in regulating inflammatory responses against bacterial infection in sepsis remains unclear. In this study, we investigated the role of GPR174 in regulating suppressive function of regulatory T cells (Treg cells) and the underlying mechanism of Gpr174-deficient Treg cells in controlling cytokine storm of sepsis. We showed that Gpr174-dedicient mice were resistant to inflammatory shock induced by lipopolysaccharide (LPS) and cecal ligation and puncture (CLP). Moreover, Gpr174 was highly expressed in Treg cells, and its deficiency in mice promoted the expression of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and interleukin (IL)-10 in Treg cells. By using the LPS-induced sepsis model, we demonstrated that anti-inflammatory macrophages (M2 macrophages) induction was Treg cell-dependent and Gpr174-deficient Treg cells protected mice against sepsis-induced lung damage through prompting M2 macrophages polarization. In vitro, Gpr174-deficient Treg cells also promoted the polarization of macrophages toward M2 cells and dampened the secretions of pro-inflammatory cytokines (IL-6 and tumor necrosis factor-α (TNF-α)) in macrophages. In conclusion, these findings suggested that GPR174 plays an important role in the initial period of sepsis through the regulation of macrophage polarization and pro- and anti-inflammatory cytokine secretions. Therefore, GPR174 may be a promising target for therapeutic agents to regulate inflammatory disorders.