Sepsis is a life-threatening condition resulting from bacterial or fungal infections. Common treatments for sepsis, such as antibiotic therapy, are far from satisfactory. Because endotoxin (LPS) is a major pathogenic factor in sepsis caused by gram-negative bacterial infections, neutralization of LPS is a promising therapeutic target. To effectively eliminate LPS, in the current study, a macrophage-mimetic hybrid liposome (M-Lipo) was developed by fusing a macrophage membrane (M-membrane) with artificial lipids. The M-membrane could provide an intrinsic binding site for LPS. The artificial PEGylated lipid could stabilize the natural membrane and prolong the circulation of M-Lipo in the bloodstream. These two membranes could complement one another and extend their biofunction as they were integrated. The results showed that M-Lipo had surface proteins similar to those of macrophages and could substantially adsorb LPS. With the help of the PEGylated lipids, M-Lipo presented much better stability than the bare M-membrane vesicle. In addition, the pharmacokinetic results revealed that M-Lipo clearly had longer retention (similar to 16%) in blood (at 12 h) than the natural M-membrane (similar to 3.3%). By combining these properties, the hybrid M-Lipo not only reduced the toxicity of LPS in vitro but also protected the mouse against endotoxic shock in vivo. In conclusion, the hybrid liposome M-Lipo has the advantages of both natural membranes and artificial materials, eventually leading to the successful treatment of sepsis.