Cholecyst‐derived extracellular matrix (CEM) is a fibro‐porous decellularized serosal layer of porcine gall‐bladder. CEM loses 90% of its weight at 48 h of in vitro collagenase digestion, but takes two months to be completely resorbed in vivo. Carbodiimide (EDC) crosslinking helps tailoring CEM's in vitro collagenase susceptibility. Here, the efficacy of EDC crosslinking on tailoring in vivo biodegradability of CEM is reported. CEM crosslinked with 0.0005 and 0.0033 × 103M of EDC/mg that lose 80% and 0% of their weight respectively to in vitro collagenase digestion, were present even after 180 days in vivo. Quantitative histopathology using stereology methods confirmed our qualitative observation that even a tiny degree of crosslinking can significantly prolong the rate of in vivo degradation and removal of CEM.