Sepsis-associated brain dysfunction (SABD) is a critical neurological complication with high mortality, yet its pathogenesis remains poorly understood. This study investigated the role of estrogen-related receptor α (ERRα) in SABD pathogenesis using ERRα knockout (KO) mice and cecal ligation and puncture (CLP) models. We found that ERRα KO mice exhibited improved survival rates, milder neurological symptoms, reduced pro-inflammatory cytokine production (TNF-α, IL-1β), and increased anti-inflammatory cytokine (IL-10) levels compared to wild-type controls. Additionally, ERRα deficiency promoted microglial M2 polarization and attenuated ferroptosis, as evidenced by decreased iron accumulation, reduced lipid peroxidation, and normalized mitochondrial morphology. Mechanistically, these protective effects were mediated through inhibition of the NF-κB signaling pathway. In vitro studies with ERRα knockdown in LPS-stimulated BV2 microglia confirmed these findings. Our results suggest that ERRα as a critical regulator of microglial function in SABD through coordinated control of inflammatory responses, polarization states, and ferroptosis, suggesting that targeting ERRα may represent a promising therapeutic strategy for SABD treatment.