Since the emergence of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4 Goose/Guangdong lineage in Europe in 2014, an unprecedented outbreak occurred during the 2021–2022 epidemiological year, causing mass mortalities in wild birds, including birds of prey, but also increasingly affecting Charadriiformes, which has imposed substantial ecological and infection pressure at the wild-bird–poultry and avian–mammalian interface. Neurological signs have been associated with higher fatalities in birds but pathological examinations of natural cases, including viral distribution, are currently lacking. In this study, we have thoroughly assessed the histopathological lesions and antigen distribution by immunohistochemistry (IHC) from 115 PCR-positive wild birds that died naturally from HPAI, including Charadriiformes, birds of prey, gamebirds, waterfowl and captive wild birds. The commonest histological lesion was pancreatic necrosis followed by splenic necrosis, encephalitis or neuronal necrosis, myocardial necrosis or myocarditis, necrosis of the respiratory tract and hepatic necrosis. Overall, 96 birds tested positive by IHC in multiple organs and most of the viral antigen was detected in the brain followed by the respiratory tract, heart, pancreas and kidney. In the brain, viral antigen was most commonly detected in neurons, neuropil and endothelium. In conclusion, HPAI-associated mortality in different wild birds can be associated with multisystemic viral dissemination and tissue damage, with endothelial tropism being a key feature in neuroinvasion and disease pathogenesis.