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Mitochondrial dysfunction is involved in the pathogenesis of sepsis-induced multiple organ dysfunction syndrome (MODS). Mitochondrial quality control (QC) is characterized by self-recovering mitochondrial damage through mitochondrial biogenesis, mitophagy, and fission/fusion. Heme oxygenase (HO)-1 acts as a signaling molecule to modulate inflammation. The present study elucidated the cytoprotective mechanisms of HO-1 in sepsis, particularly focusing on toll-like receptor (TLR)4-mediated mitochondrial QC. Mice were subjected to sepsis by cecal ligation and puncture (CLP). The mice were injected intraperitoneally with hemin (10 mg/kg) at 12 h before CLP or zinc protoporphyrin IX (ZnPP; 30 mg/kg) at 2 h before CLP. The serum and tissues were collected 6 h after CLP. Mortality, MODS, and proinflammatory cytokines increased in septic mice. These increases were augmented by ZnPP but attenuated by hemin. Hemin decreased mitochondrial lipid peroxidation and mitochondrial dysfunction. Hemin enhanced mitochondrial biogenesis, as indicated by increased levels of peroxisome proliferator-activated receptor-γ coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A (TFAM). Hemin also enhanced mitophagy, as indicated by decreased PTEN-induced putative kinase 1 (PINK1) level and increased Parkin level. Hemin decreased fission-related protein, dynamin-related protein 1 (DRP1), and increased fusion-related protein, mitofusin 2. Hemin attenuated the increased TLR4 expression. TAK-242, a TLR4 antagonist, attenuated mortality, inflammatory response, and impaired mitochondrial QC. Our findings suggest that HO-1 attenuates septic injury by modulating TLR4-mediated mitochondrial QC.