The Mediterranean Sea is recognized as one of the most polluted areas by floating plastics. During the Tara Mediterranean expedition, an extensive sampling of plastic debris was conducted in seven ecoregions, from Gibraltar to Lebanon with the aim of providing reliable estimates of regional differences in floating plastic loads and plastic characteristics. The abundance, size, surface, circularity and mass of 75,030 pieces were analyzed and classified in a standardized multi-parameter database. Their average abundance was 2.60 × 105 items km−2 (2.25 × 103 to 8.50 × 106 km−2) resulting in an estimate of about 650 billion plastic particles floating on the surface of the Mediterranean. This corresponds to an average of 660 metric tons of plastic, at the lower end of literature estimates. High concentrations of plastic were observed in the northwestern coastal regions, north of the Tyrrhenian Sea, but also off the western and central Mediterranean basins. The Levantine basin south of Cyprus had the lowest concentrations. A Lagrangian Plastic Pollution Index (LPPI) predicting the concentration of plastic debris was validated using the spatial resolution of the data. The advanced state of plastic degradation detected in the analyses led to the conclusion that stranding/fragmentation/resuspension suggests it is a key process in the dynamics of floating plastic in Mediterranean surface waters. This is supported by the significant correlation between pollution sources and areas of high plastic concentration obtained by the LPPI.