AbstractThis work aims at investigating intensively the effects of organosilicone species and their dosage on the physicochemical and particularly the in vitro degradation properties of gelatin hybrids. We prepared various porous organosilicone modified gelatin hybrids with epoxy‐polydimethylsiloxane (PDMS) and/or glycidoxypropyltrimethoxysilane (GPTMS) and further systematically investigated their degradation behaviors in simulated physiological environments. It was found that the chemical composition, thermal stability, crosslinking degree, mechanical properties and porous structure of the gelatin hybrids could be tuned by adjusting the amount of PDMS and GPTMS. More importantly, degradation rates of the gelatin hybrids were reduced with increasing content of GPTMS, implying that the degradation behaviors could be controlled by tailoring the chemical interaction between the gelatin and organosilicone moieties. In addition, gelatin hybrids modified with both PDMS and GPTMS (PGs‐GE) were demonstrated as a homogeneous hybridization, and their maximum weight losses met the typical healing period of a normal skin wound. Noticeably, the P1G1‐GE hybrid with PDMS to GPTMS molar ratio 1:1 exhibited appropriate weight loss, integrity of pore structure and synchronous dissolution of silicon and protein during the degradation process, indicating a homogeneous degradation behavior. Furthermore, both the original and degraded P1G1‐GE hybrid exhibited favorable cytocompatibility in vitro. The findings will be helpful for further insight into the in vivo degradation of gelatin hybrids, suggesting their potential application as skin regeneration scaffolds. © 2019 Society of Chemical Industry