Influenza A hemagglutinin (HA), neuraminidase, and/or M2e-containing virus-like particles (VLPs) induce immune responses that contribute to protection against multiple influenza A virus subtypes. In this study, we investigated the protective efficacy of influenza A/H1H3 VLPs against influenza B virus infections (B/Colorado/06/2017 and B/Malaysia/2506/2004, Victoria lineage) in mice. A/H1H3 VLP immunization elicited protection against lethal challenge infections with both B/Colorado and B/Malaysia, significantly reducing lung viral loads and ensuring 100% survival of immunized mice. Sera from A/H1H3VLP-immunized mice recognized inactivated B/Colorado and B/Malaysia virus antigens and enhanced Fc receptor-mediated antibody-dependent cellular cytotoxicity (ADCC) responses. Notably, immune sera reacted with HA, HA1, and HA2 antigens from both B/Colorado and B/Malaysia viruses. A/H1H3VLP immunization also induced lung IgG and IgA antibody responses against HA, HA1, and HA2 of both B viruses, as well as antibody-secreting cell responses (ASC), germinal center B (GC B) responses, and CD4+ T cell responses. Additionally, A/H1H3VLP immunization significantly suppressed pro-inflammatory cytokines responses (IFN-γ, IL-6). These results suggest that A/H1H3 VLP hold promise as a candidate for a universal influenza vaccine capable of providing cross-protection against influenza B virus infection.