In late 2021, Eurasian-lineage highly pathogenic avian influenza (HPAI) A(H5N1) viruses from HA clade 2.3.4.4b were first detected in the United States, marking a significant milestone in their global spread. . These viruses have caused severe morbidity and mortality in poultry and have been found in various wild birds, mammals, and even dairy herds, leading to decreased milk productiondetected in numerous wild and domestic animals, including cows and humans. Notably, Infected infected cows transmitted the virus to cats, causing neurological symptomsextreme pathogenicity and death and recently, a pig cohabiting with poultry tested positive. While human-to-human spread of the virus has not been recorded, efficient transmission of the bovine-origin virus has also led to extreme pathogenicity and death in ferrets’ models. Recently, markers in PB2 (E627K) and HA (E186D, Q222H), indicating mammalian adaptation mutations, were detected in a patient manifesting critical illness in Canada. These, combined by instances of interspecies spread of the virus, Though the virus poses minimal risk to the general population, as no mammalian adaptation mutations or evidence of human-to-human transmission have been detected, instances of interspecies transmission have raised global public health concerns. These include cases where the virus spread from poultry and cows to humans, with respiratory transmission observed in bovine-origin viruses. This could highlights the potential for the virus to successfully adapt to mammals, posing a serious risk of a global outbreak. A One Health approach is, thereby, necessary to monitor and control the outbreak. This review aims to analyze the epidemiology, transmission, and ecological impacts of HPAI A(H5N1) clade 2.3.4.4b in the U.S., identify knowledge gaps, and inform strategies for effective outbreak management and mitigation.