Highly pathogenic Avian Influenza (HPAI) viruses continue to cause severe economic losses in poultry species worldwide. HPAI virus of subtype H5N1 was reported in Egypt in 2006, and despite vaccination efforts, the virus has become endemic. The current study aims to evaluate the efficacy of a virus-like particle (VLP) based vaccine in vivo using specific pathogen-free (SPF) chickens. The vaccine was prepared from the HPAI H5N1 virus of clade 2.2.1.2 using the baculovirus expression system. The VLPs were quantitated and characterized, including electron microscopy. In addition, the protection level of the VLPs was evaluated by using two different regimens, including one dose and two-dose vaccinated groups, which gave up to 70% and 100% protection level, respectively. The results of this study emphasize the potential usefulness of the VLPs-based vaccine as an alternative vaccine candidate for the control of AIV infection in poultry.