Gasdermin-D (GSDMD) is activated by caspase cleavage at (GSDMD 1–275) to form membrane pores, leading to unconventional secretion of proinflammatory cytokines. Viral proteases are essential intracellular enzymes that cleave viral polyproteins for replication. By TAILS and interactomics we identified a diverse array of host proteins for immune and antiviral defence evasion. As no viral proteases are reported to be extracellular, exploring extracellular substrates of viral proteases has been overlooked. We establish that 3CLpro and nucleocapsid protein are secreted from SARS-CoV-2 infected cells by unconventional protein secretion through GSDMD and GSDME pores formed by viral 3CLpro in concert with host caspase cleavages. MS/MS identified three 3CLpro cleavage sites in gasdermin-D (GSDMD). Cleavage at LH270↓NF generates a pore-forming N-terminal domain (GSDMD 1–270) that leads to 3CLpro release from cells. Non-cleavable mutant GSDMD established the relative contributions of caspase and 3CLpro cleavage events. Excessive GSDMD 1–270 pore formation increased lactate dehydrogenase release, indicative of pyroptotic cell death in concert with cell membrane lytic rupture. Glycine cytoprotection prevented lysis, resulting in increased GSDMD-mediated 3CLpro secretion. 3CLpro was abundant in conditioned media of SARS-CoV-2-infected cells and was detected in bronchoalveolar lavage fluid of wild-type SARS-CoV-2-infected mice and decreased in Gsdmd–/–Gsdme–/– mice. Extracellular 3CLpro retained proteolytic activity in serum, dampened platelet activation and aggregation, and inactivated interferon-lambda1 by two cleavages. Linking intracellular 3CLpro cleavage of GSDMD with 3CLpro secretion and extracellular activity reveals unexpected viral protease-driven immune evasion mechanisms. To our knowledge, the secretion of a viral protease with potential pathologic consequences has not been previously reported.