<p>In the current study, a biocompatible scaffold was developed using propolis, guar gum, and porcine dermal acellular tissue matrix. The components of the scaffold were physically crosslinked via a freeze-thaw process to attain optimum porosity. The scaffold was evaluated for its surface morphology, porosity, degradation, and in vivo potential for skin tissue regeneration. The molecular pathway involved in tissue regeneration efficacy was assessed by the molecular docking method. Comprehensive characterization using FTIR, XRD, DSC, and TGA demonstrated the compatibility among the components of the scaffold. Surface morphology analysis by FESEM and optical profilometry revealed optimum surface roughness and porosity for cell attachment and viability. Additionally, in vivo studies showed promising results in promoting wound healing and skin tissue regeneration with minimal inflammatory response. The docking studies revealed that different components of propolis, in coordination with guar gum and porcine dermal acellular tissue matrix, activated the healing and skin tissue regeneration process by binding with fibroblast growth factor and matrix metalloproteinases. The results of the study demonstrated that the developed scaffold possesses desirable physicochemical and biological properties, making it a potential candidate for skin tissue engineering applications.</p> Graphical abstract <p></p>