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Decellularized small intestine submucosa (dSIS) is a promising biomaterial for promoting tissue regeneration. Isolated from the submucosal layer of animal jejunum, SIS is rich in extracellular matrix (ECM) proteins, including collagen, laminin, and fibronectin. Following mild decellularization, dSIS becomes an acellular matrix that supports cell adhesion, proliferation, and differentiation. Conventional dSIS matrix is usually obtained by thermal crosslinking, which yields a soft scaffold with low stability. To address these challenges, dSIS is modified with methacrylate groups for photocrosslinking into stable hydrogels. However, dSIS has not been modified with clickable handles for orthogonal crosslinking. Here, the development of norbornene‐modified dSIS, named dSIS‐NB, via reacting amine groups of dSIS with carbic anhydride in acidic aqueous reaction conditions is reported. Using triethylamine (TEA) as a mild base catalyst, high degrees of NB substitution on dSIS are obtained. In addition to describing the synthesis of dSIS‐NB, its adaptability in orthogonal hydrogel crosslinking for cancer and vascular tissue engineering is explored. Impressively, compared with physically crosslinked dSIS and collagen matrices, orthogonally crosslinked dSIS‐NB hydrogels supported rapid dissemination of cancer cells and superior vasculogenic and angiogenic properties. dSIS‐NB is also exploited as a versatile bioink for 3D bioprinting. [ABSTRACT FROM AUTHOR]