This report describes the pathology and tissue distribution of avian influenza (AI) antigens by immunohistochemistry (IHC) in the tissues of commercial layer quail from a natural outbreak of low pathogenic avian influenza (LPAI) H5N8. LPAI virus H5N8 of North American lineage was diagnosed in commercial Japanese quail hens (Coturnix coturnix japonica) in California based on serology, reverse-transcriptase real-time polymerase chain reaction, virus isolation, and sequencing. The sudden increase in mortality in a flock of laying quail hens had prompted the submission of 15 live and 5 dead, 10- to 15-wk-old quail to the California Animal Health and Food Safety Laboratory System, Turlock branch in the beginning of April 2014. There was mild bilateral swelling of the eyelids and greenish diarrhea in 4/15 live quail submitted. On postmortem examination, there were severe, extensive hemorrhages and multifocal, confluent pale foci in the pancreas in 10/20 birds. Liver gross lesions in five birds ranged from a few pale areas to numerous disseminated foci. Histology revealed moderate to severe necrosis of acinar cells in the pancreas with little or no inflammation in most of the birds. Livers had acute multifocal coagulative necrosis of hepatocytes with fibrin exudation and infiltration of few to large numbers of heterophils and lymphocytes randomly scattered throughout. The AI virus was detected in the nucleus and cytoplasm of pancreatic acinar cells and hepatocytes by IHC targeting the nucleoprotein of the AI virus. A few birds had AI antigen in the reticuloendothelial cells of the spleen, endothelial cells of the lungs, epithelium of the respiratory mucosa, and lamina propria of the intestine. The severity of the lesions observed in this natural outbreak of LPAI in quail was higher than that expected for the pathotypic presentation in this species.