After nearly a decade without reported human A/H5N1 infections, Cambodia faced a sudden resurgence with 16 cases between February 2023 and August 2024, all caused by A/H5 clade 2.3.2.1c viruses. Fourteen cases involved a novel reassortant A/H5N1 virus with gene segments from both clade 2.3.2.1c and clade 2.3.4.4b viruses. The emergence of this novel genotype underscores the persistent and ongoing threat of avian influenza in Southeast Asia. This study details the timeline and genomic epidemiology of these infections and related poultry outbreaks in Cambodia.