Understanding plastics’ harmful impacts on wildlife would benefit from the application of hypothesis agnostic testing commonly used in medical research to detect declines in population health. Adopting a data-driven, proteomics approach, we assessed changes in 745 proteins in a free-living non-model organism with differing levels of plastic exposure. Seabird chicks heavily affected by plastic ingestion demonstrated a range of negative health consequences: intracellular components that should not be found in the blood were frequently detected, indicative of cell lysis. Secreted proteins were less abundant, indicating that the stomach, liver, and kidneys are not functioning as normal. Alarmingly, these signatures included evidence of neurodegeneration in < 100-day old seabird chicks with high levels of ingested plastic. The proteomic signatures reflect the effects of plastic distal to the site of exposure (i.e., the stomach). Notably, metrics commonly used to assess condition in wildlife (such as body mass) do not provide an accurate description of health or the impacts of plastic ingestion.