Few studies have focused so far on plastic ingestion by sharks in the Mediterranean Sea. The aim of this paper was to determine, for the first time, the plastic litter ingested by blue sharks (Prionace glauca), categorized as “Critically Endangered” in the Mediterranean Sea by IUCN, caught in the Pelagos Sanctuary SPAMI (North-Western Mediterranean Sea). The analysis of the stomach contents was performed following the MSFD Descriptor 10 standard protocol implemented with FT-IR spectroscopy technique. The results showed that 25.26% of sharks ingested plastic debris of wide scale of sizes from microplastics (<5 mm) to macroplastics (>25 mm). The polyethylene sheetlike user plastics, widely used as packaging material, are the most ingested debris. This research raises a warning alarm on the impact of plastic debris on a threatened species, with a key role in the food web, and adds important information for futures mitigation actions.