Highly pathogenic avian influenza (HPAI) A(H5) viruses have caused sporadic human infections since 1997, with recent detections in the Americas and Asia. However, the evolutionary dynamics of different HPAI A(H5) viruses at the animal-human interface, along with their associated disease severity, propensity for animal-to-human (zoonotic) spillover, and human-to-human transmission potential, remain unclear. Here, we combine available genetic and epidemiological data with mechanistic models to better understand global spread of HPAI A(H5) viruses that spilled over to humans in 1997–2025. Analysis of 7445 subsampled hemagglutinin gene sequences revealed frequent regional succession of HPAI A(H5) virus clades that varied by geographic location. The 1104 reported human HPAI A(H5) cases exhibited subtype- and clade-specific heterogeneity in age, gender, and exposure sources (p < 0.001). After adjusting for under-reporting, we estimated case-fatality risk to be low for HPAI A(H5N1) clade 2.3.4.4b (0.7%, 95%CI 0.02–3.9%) and for A(H5N6) clades 2.3.4x (0%, 0–1.1%) and 2.3.4.4b (1.6%, 0.7–3.2%), compared with other A(H5) clades (range: 4.7–15.0%). We also show that, while the transmissibility of HPAI A(H5) viruses between humans remains very low to date (mean Rt: 0.10–0.23), zoonotic transmission has increased with the emergence of bovine-origin clade 2.3.4.4b (incidence: 7.85 per million people per year), relative to other avian-origin A(H5) clades (range: 1.54–5.04 per million people per year). Although other factors such as exposure sources, routes of transmission, immune function, underling medical conditions, and clinical management can influence outcomes of case-patients, these findings highlight the ongoing pandemic threat posed by HPAI A(H5) viruses and the need for ongoing comprehensive surveillance, genotypic and phenotypic characterization, and preparedness.