Autologous skin grafts, which can cause donor site morbidity, are currently used to treat deep wounds. To improve the regeneration of poorly healing wounds, cell-derived extracellular matrix (ECM) scaffolds are garnering great research interest due to their associated lower risks of pathogen transfer and immune rejection. However, the mechanical properties of cell-derived ECM scaffolds are inferior when compared to those of tissue-derived ECM scaffolds. To overcome this drawback, different amounts (10, 20, 50, and 100 μg mL-1) of graphene oxide (GO) and genipin (1% w/v) were applied to adipose stem cell (ASC)-derived ECM sponges. There are still only a few studies employing cell-derived extracellular matrices as biomimetic scaffolds for biomedical applications. The aim of our study was to develop biocompatible, biodegradable, low immunogenic, and genipin-crosslinked ASC-derived ECM sponges containing a suitable amount of GO for skin-tissue engineering. Sponges were fabricated using cultures of ASCs, cell sheets, and decellularization of an ASC cell sheet, freeze-thawing, and crosslinking in a sequential manner. Scanning electron microscopic analyses of the sponges demonstrated a highly porous microstructure with a pore size of 71.22 ± 19.52 μm. The in vitro degradation rate was found to be significantly higher in the non-crosslinked ECM sponges and pure ECM sponges than in the genipin-crosslinked ECM sponges. During an in vivo study, we investigated the material feasibilities and degradability of the constructed ECM sponges as a suitable skin tissue-engineering scaffold in a xenogenic animal (rat) model for 4 weeks. After subcutaneous implantation, the ECM sponges containing a medium amount of GO showed appropriate biodegradation with a lower inflammatory reaction. Hence, the fabricated ECM sponges might be a suitable xenogenous skin substitute for full-thickness skin defects and in other future soft-tissue engineering applications, such as healing partial tears of the anterior cruciate ligament.