Understanding plastics’ harmful impacts has been hampered by the application of overly simplistic tools, mostly focusing on a single response variable which limits our ability to detect changes in wildlife health. Adopting a data-driven, proteomics approach, we assessed changes in 745 proteins in a non-model organism with differing levels of plastic exposure. In high plastic impacted seabirds, we observed a range of negative health consequences: intracellular components that should not be found in the blood were frequently detected, indicative of cell lysis. There was significant evidence of neurodegeneration, and secreted proteins were less abundant, indicating the kidney and particularly the liver are not functioning as normal. The proteomic signatures reflect the effects of plastic distal to the site of exposure (i.e., the stomach) demonstrating plastic shedding and leachate toxicity in the plasma. Notably, metrics commonly used to assess body condition do not provide an accurate description of health or plastic impaction.