Antibodies to Ebola virus glycoprotein (EBOV GP) represent an important correlate of the vaccine efficiency and infection survival. Both neutralization and some of the Fc-mediated effects are known to contribute the protection conferred by antibodies of various epitope specificities. At the same time, the role of the complement system in antibody-mediated protection remains unclear. In this study, we compared complement activation by two groups of representative monoclonal antibodies (mAbs) interacting with the glycan cap (GC) or the membrane-proximal external region (MPER) of the viral sole glycoprotein GP. Binding of GC-specific mAbs to GP induced complement-dependent cytotoxicity (CDC) in the GP-expressing cell line via C3 deposition on GP in contrast to MPER-specific mAbs that did not. Moreover, treatment of cells with a glycosylation inhibitor increased the CDC activity, suggesting that N-linked glycans downregulate CDC. In the mouse model of EBOV infection, depletion of the complement system by cobra venom factor led to an impairment of protection exerted by GC-specific but not MPER-specific mAbs. Our data suggest that activation of the complement system is an essential component of antiviral protection by antibodies targeting GC of EBOV GP.