From October 2020 to July 2021, five different subtypes (H5N8, H5N5, H5N1, H5N4, and H5N3) and seven genotypes of highly pathogenic avian influenza viruses (HPAIV) belonging to clade 2.3.4.4b were detected in a broad array of avian hosts in Germany. Initial incursion by wild birds with an unprecedented involvement of charadriiforme species at the Wadden Sea coast only carrying subtype H5N3, lateral spread between poultry with detection of novel reassortants and mixed infections in poultry holdings, suspected spillback of HPAIV from poultry to wild birds, and detection of HPAIV-infected wild birds during the following summer in 2021 were hallmarks of this epizootic. Local reassortment events with low pathogenic AIV strains were detected by phylogenetic analyses, with a dominating HP H5N8 and later HP H5N1 strain responsible for most cases. In addition, the first-ever described HPAIV strain of subtype H5N4 could be genetically characterized.