Clade 2.3.4.4 H5Nx subtype avian influenza viruses (AIVs) have circulated in poultry and wild birds worldwide. Recently, an increasing number of H5Nx human infection cases have been reported occurred. Live attenuated influenza vaccines demonstrate more advantages than other types of vaccines, such as ease of administration, elicitation of systemic immune responses, and the ability to generate breadth protection. However, the attenuated viruses also bear the risk of reassortment with the wild-type influenza A virus. To overcome this reassortment problem, we designed and constructed Clade 2.3.4.4 H5 chimeric cold-adapted attenuated influenza vaccines (CAIVs) by introducing the hemagglutinin ectodomains of H5N6 into a cold-adapted attenuated master donor of an influenza B virus. These H5 CAIVs induce humoral antibody response, mucosal immune response, and cellular immune response in mice models. After two doses were administered in mice, H5 CAIVs provided cross-protection responses with 100% survival against wild-type Clade 2.3.4.4 H5 subtype AIVs. The immunized mice exhibited more significant reductions of lung viral titers or lung pathology than those in the mock group mice. In ferret models, Clade 2.3.4.4b and 2.3.4.4h H5 CAIVs produced a cross-protective efficacy against wild-type Clade 2.3.4.4b and Clade 2.3.4.4h H5 AIVs. The findings of the current study indicate that our H5 CAIVs may have the potential to prevent and control H5Nx influenza viruses in humans.IMPORTANCEClade 2.3.4.4 H5Nx avian influenza viruses (AIVs) have circulated globally and caused substantial economic loss. Increasing numbers of humans have been infected with Clade 2.3.4.4 H5N6 AIVs in recent years. Only a few human influenza vaccines have been licensed to date. However, the licensed live attenuated influenza virus vaccine exhibited the potential of being recombinant with the wild-type influenza A virus (IAV). Therefore, we developed a chimeric cold-adapted attenuated influenza vaccine based on the Clade 2.3.4.4 H5 AIVs. These H5 vaccines demonstrate the advantage of being non-recombinant with circulated IAVs in the future influenza vaccine study. The findings of our current study reveal that these H5 vaccines can induce cross-reactive protective efficacy in mice and ferrets. Our H5 vaccines may provide a novel option for developing human-infected Clade 2.3.4.4 H5 AIV vaccines.