Severe carbon monoxide (CO) poisoning can induce structural and functional damage to the nervous system, resulting in persistent cognitive impairments. Properly terminating inflammation caused by neuronal damage is essential for tissue repair. Macrophages clear cell corpses and fragments through efferocytosis and produce cytokines to coordinate the immune response, thus promoting neuronal repair and regeneration. However, within the microenvironment of the CO-affected nervous system, macrophage efferocytosis is disrupted. Our study found that macrophages regulate efferocytosis by releasing Cardiotrophin-like cytokine factor 1 (CLCF1), which modulates the NF-κB pathway in both macrophages and microglia, thereby controlling inflammation and promoting nervous system repair. Furthermore, efferocytosis regulates the secretion of cytokines such as TNF-α, IL-1β, and IL-10, promoting M2 polarization of macrophages, which aids in neuronal repair and regeneration. Regulating macrophage CLCF1 expression also leads to improvements in the memory, learning, and motor abilities of rats poisoned with CO.