In 2023, high pathogenicity avian influenza (HPAI) H5N1 outbreaks caused mass mortality events affecting pinnipeds throughout South America. Here, we present the clinical, pathological, immunohistochemical, and molecular findings associated with HPAI H5N1 infection in 3 South American sea lions (Otaria flavescens) and 1 southern elephant seal (Mirounga leonina) stranded during the outbreak in Chubut, Argentina. Neurological signs were observed in 2 sea lions, with 1 also exhibiting respiratory distress. Necropsies were conducted on all 4 animals. Neuropathology revealed mild-to-severe lymphohistiocytic (2/4) to mixed neutrophilic (2/4) meningoencephalitis with neuronal necrosis, neuronophagia, glial cell proliferation, multifocal hemorrhage, and perivascular cuffing in all animals. Novel findings for HPAI H5N1-infected pinnipeds included choroid plexitis (2/4) and myelitis (2/4). Immunohistochemistry for viral nucleoprotein was positive in 3 of 4 animals and involved neurons (3/3), glial cells (3/3), and ependymal cells (2/3). Viral-related systemic findings included multifocal necrotizing myocarditis in the elephant seal and multifocal necrotizing placentitis in a sea lion, with HPAI virus detected within fetal tissues. Pulmonary lesions were minimal and were limited to multifocal necrosis of bronchial glands in 1 sea lion. HPAI H5 clade 2.3.4.4b virus was confirmed by polymerase chain reaction and sequencing in all animals. These findings indicate a predominance of central nervous system involvement in HPAI H5N1-infected pinnipeds and expand the recognized spectrum of virus-associated lesions, identifying novel tissue tropisms and transmission routes.