For the past decade, several recombinant Newcastle disease viruses (rNDV) have been used as a vector to express native or modified avian influenza (AI) hemagglutinins (HA) in order to give preventive protection against highly pathogenic avian influenza (HPAI) H5N1 viruses. Obtained protections were dependent on the age of the chickens, on the constructs and, in particular, on the homology between the HA that was inserted and the challenge strains. The objective of this study was to investigate the vaccine efficacy of a recombinant NDV La Sota-vectored vaccine expressing an Asian clade 1 H5 ectodomain (rNDV-H5) vaccine expressing a modified H5 ectodomain from an HPAI clade 1 H5N1 isolate as vaccine for 1-day-old specific-pathogen-free chickens. The inoculation route (oculonasal vs. drinking water), the dose-effect, and the protective range of this rNDV-H5 vaccine were studied. Both routes of vaccination induced an H5 serologic response and afforded a high degree of clinical protection against an Asian clade 1 HPAI H5N1 (AsH5N1) challenge without a significant difference between inoculation routes. A clear dose-effect could be demonstrated. Furthermore, when evaluating the protective range against antigenically divergent descendants of the Asian clade 1 HPAI H5N1 lineage, namely two Egyptian clade 2.2.1 H5N1 strains, the vaccine efficacy was less satisfactory. The rNDV-H5 vaccine provided good clinical protection and reduced viral shedding against Egyptian 2007 challenge but was unable to provide a similar protection against the more antigenically divergent Egyptian 2008 strain.