Avian influenza A viruses, especially highly pathogenic avian influenza (HPAI) viruses, pose a significant public health threat, and a multivalent vaccine is the primary prophylactic measure to control these viruses. To establish such a vaccine, we generated two multivalent vesicular stomatitis virus (VSV)-based vaccine candidates that simultaneously target H5N1 hemagglutinin (H505 or H522) and the ectodomain of matrix protein 2 (M2e) and characterized their ability to induce protective immune responses. Our results revealed that vaccine immunization induced high humoral immune responses against both the HPAI hemagglutinin (HA) protein and the M2 protein in mice. Intriguingly, vaccine-immunized mouse sera exhibited highly efficient neutralizing activity against the corresponding H5 pseudovirus and mediated potent and broad antibody-dependent cellular cytotoxicity (ADCC) activity against M2e derived from human and avian influenza H5, H1, H3, and H7 viruses. Furthermore, both intranasal (IN) and intramuscular immunization (IM) of V-EtM2e/H522 provided efficient protection against HPAI H5N1 virus challenge in mice, with a 100% survival rate and a nondetectable viral load in several tissues. Notably, noninvasive mucosal IN delivery achieved protection equal to that of IM delivery at a 100-fold lower immunizing dose. These findings provide strong evidence for the effectiveness of a multivalent VSV-based vaccine against human (avian) influenza A viruses.