Highly pathogenic avian influenza (HPAI) H5 viruses have recently been documented in mammals including humans, posing a major threat to global public health. To prevent a potential H5 pandemic, it is critical to elucidate the antigenic evolutionary pattern and identify key drivers underlying its evolution. In this study, we constructed a comprehensive antigenic map of H5 influenza viruses spanning their evolutionary history for the first time, revealing three distinct antigenic clusters (AC1, AC2, and AC3) with no cross-neutralization. In contrast to its sequential genetic evolution, AC3 lies between AC1 and AC2 in antigenic space. This divergence stems from two distinct mutation patterns at six key amino acid positions: (1) persistent mutations at positions 88 (N?>?R?>?S), 199 (D?>?N?>?S), and 205 (K?>?N?>?D), and (2) reversible mutations at positions 131 (Q?>?L?>?Q), 139 (S?>?P?>?S), and 289 (N?>?H?>?N). Moreover, single mutations at positions 205 and 289 can lead to significant immune escape. The risk clade of current interest, 2.3.4.4b belongs to AC2 and remains sensitive to current AC2-targeted vaccine strains. Additionally, clades 2.3.2.1c of AC1 and 2.3.4.4h of AC3 are also prevalent and capable of human infection, necessitating continuous surveillance of their epidemiological dynamics. These findings not only reveal the antigenic evolution mechanism of H5 influenza unseen in other influenza viruses, but also provide important guidance for vaccine strain selection and broad-spectrum vaccine development.