The connection between COVID-19 and coagulopathy has been clear since the early days of SARS-CoV-2 pandemic. Although available data indicate that systemic inflammation sustains a hypercoagulant state and increases thrombotic risk, the underlying molecular mechanisms of COVID-19 associated coagulopathy remain unclear. Here we show that SARS-CoV-2 main protease (Mpro) can play a direct role in the activation of the coagulation cascade. Adding Mpro to human plasma increased clotting probability by 2.5-fold. The results of enzymatic assays and degradomics analysis indicate that Mpro triggers plasma clotting by proteolytically activating coagulation factor zymogens VII and XII at their physiological activation sites, involving Arg-Ile/Val bonds, where FVII and FXII are strategically positioned at the beginning of the extrinsic or intrinsic pathways of blood coagulation. Even though the observed cleavage sites are not compatible with the known substrate specificity of the protease, involving Gln-X bonds, the results of High Throughput Protease Screen assay unveil an extended, time-dependent, secondary specificity of Mpro for Arg-X bonds, which was further confirmed by enzymatic assays with synthetic peptide substrates containing Arg at P1 position. Overall, integrating biochemical, proteomics and structural biology experiments, we unveil a novel, additional mechanism linking SARS-CoV-2 infection to thrombotic complications in COVID-19.