Complement and Toll‐like receptors (TLRs) play key roles in the host immune response and are swiftly activated by infection or other types of immunological stress. This review focuses on the capacity of complement and TLRs to engage in signaling crosstalk, ostensibly to coordinate immune and inflammatory responses through synergistic or antagonistic (regulatory) interactions. However, overactivation or dysregulation of either system may lead—often synergistically—to exaggerated inflammation and host tissue injury. Intriguingly, moreover, certain pathogens can manipulate complement–TLR crosstalk pathways in ways that undermine host immunity and favor their persistence. In the setting of polymicrobial inflammatory disease, subversion of complement–TLR crosstalk by keystone pathogens can promote dysbiosis. Knowledge of the molecular mechanisms underlying complement–TLR crosstalk pathways can, therefore, be used productively for tailored therapeutic approaches, such as, to enhance host immunity, mitigate destructive inflammation, or counteract microbial subversion of the host response.