The present study aimed to prepare and investigate the wound healing potential of carboxymethyl cellulose (CMC)-based wafers incorporated with resveratrol (RSV)-loaded cellulose acetate butyrate (CAB) NPs. Accordingly, RSV-CAB NPs were prepared using the solvent evaporation method. The effect of different formulation parameters (polymer content, surfactant concentration, and the volume ratio of aqueous phase to organic phase) on the properties of NPs was investigated using the Box-Behnken design. Then, the optimized NPs were incorporated in wafers comprising CMC combined with hydroxyl propyl methyl cellulose (HPMC) or chitosan. Hydration capacity, porosity, adhesive strength, and hardness of the prepared nanocomposite wafers were examined. Optimized formulation was spherical, showing the particle size, polydispersity index, zeta potential, encapsulation efficiency %, drug loading %, and release efficiency % of 248.5 nm, 0.38, - 1.59, 87.58, 25.94, and 67.10, respectively. The CMC-HPMC wafers exhibited higher porosity, hydration capacity, and adhesive performance, as compared with the CMC wafers alone and CMC-chitosan wafers. Wound healing test and histological evaluation in the excisional wounds of the rats showed that the RSV-NPs-wafers were more effective as a healing accelerator, in comparison to wafers without drug or those containing the free RSV. These results demonstrated the potential of the RSV-NPs-wafer in wound healing drug delivery applications. Graphical abstract.