Methicillin‐resistant Staphylococcus aureus (MRSA) can interfere with synergistic host defenses, thus escaping from immune surveillance. Herein, a new immunotherapy strategy‐simulating complement therapy is proposed. Two artificial effectors, Tat cell penetrating peptide and wheat germ agglutinin, are utilized to develop a multifunctional complement‐mimic liposome (CML) simultaneously delivering antibiotics and orchestrating the complement system with macrophages. The CML successfully simulates the functions of the complement system, including formation of a membrane attack complex, mediation of opsonophagocytosis, and activation of phagocytes. At infection sites, CMLs are able to recognize MRSA and disrupt bacterial permeation barriers (cell walls and cell membranes). Meanwhile, CMLs attached to the surface of MRSA are able to activate the phagocytosis and immune responses of macrophages. As a result, CMLs significantly increased the bacterial activity of clarithromycin both in vitro and in macrophages. Moreover, CMLs effectively reduced the MRSA burden in three infection models, including skin abscesses, pneumonia, and bacteremia mouse models. Therefore, the CML provides a novel strategy for overcoming bacterial immune evasion and sheds light on the development of immunotherapies for infectious diseases. In this study, the complement‐mimic liposome (CML) is developed against methicillin‐resistant Staphylococcus aureus (MRSA) infection. The CML successfully simulates the functions of the complement system, including formation of a membrane attack complex, mediation of opsonophagocytosis, and activation of phagocytes. Importantly, intravenous administration of CMLs effectively reduces the MRSA burden in skin abscesses, pneumonia, and bacteremia mouse models.