Sepsis refers to a life-threatening organ dysfunction caused by a dysregulated host response to infection, with persistently high morbidity and mortality, posing a significant healthcare burden. As integral components of innate and adaptive immunity, macrophages exhibit high plasticity and can differentiate into distinct phenotypes (M1 pro-inflammatory and M2 anti-inflammatory) in response to various environmental stimuli, playing crucial roles in both the hyperinflammatory phase and late immunosuppressive phase of sepsis. The metabolic profile of M2 macrophages has gradually become a research focus, and it is regulated by a variety of enzymes and signaling pathways, including adenosine 5'-monophosphate-activated protein kinase, peroxisome proliferator-activated receptor and protein kinase RNA-like ER kinase pathways. These pivotal signaling pathways and enzymes can promote the polarization of M2 macrophages and enhance their anti-inflammatory functions by modulating the metabolism of glucose, lipid, and amino acid, thereby conferring protective effects against sepsis and providing new ideas for the targeted treatment.