Influenza is a global health concern, causing over 300,000 deaths worldwide annually. Current vaccines and natural infection mainly elicit antibodies against the variable head domain of the hemagglutinin (HA) glycoprotein. While these antibodies are highly neutralizing, the head domain constantly mutates due to selective pressure, causing the immune response to be strain-specific. Targeting the conserved HA stalk domain, however, has been shown to be a promising approach for a broadly protective vaccine. We previously demonstrated that presenting HA in an inverted orientation on virus-like particles (VLPs) significantly enhanced the induction of stalk-directed, cross-reactive antibodies compared to HA presented in a regular orientation. Here, we evaluated the protective efficacy of the inverted HA vaccine (VLP-HAinv) in mice against homologous, heterologous, and heterosubtypic influenza A virus challenges. VLP-HAinv vaccination in mice provided complete protection against homologous and heterologous H1N1 challenges as well as partial protection against a heterosubtypic challenge with bovine H5N1.