Invasion of pathogens into host cells is the key process to consequently induce the infection, which depends on the actin cytoskeleton rearrangement. Cofilin in the host cell is one of the most important actin depolymerization factor that is essential responsing to the infection of several viruses, bacteria and fungi. Pathogenic microbes can induce biphasic remodeling of the actin cytoskeleton in host cells, accompanied by changes of phosphorylation of cofilin, which results in changes of cofilin activity. The modulation of host cofilin activity by mutation, knockdown, or overexpression can effectively inhibit the infection. Here we review the function and possible regulatory mechanism of host cofilin during the process of infection.