Recently, the design of polymer nanofibers using the electrospinning process has attracted much interest. Particularly the use of natural polymers has promoted many advantages in their biomedical applications. However, the combination of multiple natural polymers remains a great challenge in terms of electrospun production and applied performance. From this perspective, the current investigation highlights the study of the preparation of electrospun nanomaterial scaffolds based on combined natural polymers for improved wound healing performance. First, we have synthesized a crosslinked polymer by reacting microcrystalline cellulose (MC) and chitosan (CS) biopolymer the intermediate of citric acid as a crosslinking agent. Then a natural propolis biomolecule was incorporated into the polymer network. Different MC/CS blend ratios of 90/10 and 70/30 were then used and various machine parameters were optimized to obtain nanofiber scaffolds with excellent strength and structures. SEM, IR, physicochemical, mechanical, and morpho-logical characterization were then performed. SEM evaluation revealed homogeneous and bead-free nanofibrous structures, with well-defined morphology and a random deposition that could accurately mimic the extracellular matrix of native skin. The calculated average nanofiber diameters for the MC/CS blend ratios at 90/10 and 70/30 were 431.4 and 441.2 nm, respectively. The results showed that when the chitosan amount increased, larger nanofibers with narrow diameter distribution appeared. The prepared nanomaterials had a significant and close water vapor permeability of about 1735.12 and 1698.52 g per m per day for the two blend ratios of 90/10 and 70/30, respectively. The examination of swelling behavior revealed a noteworthy enhancement in hydrophilicity, a necessary attribute for improved healing efficacy. FT-IR analysis confirmed the success and the stability of the chemical crosslinking reaction between the two biopolymers before nanofiber conception. Excellent mechanical properties were acquired, based on the chitosan content. Both developed nanofiber scaffolds exhibited high tensile strength and Young's modulus values. The incorporation of 30% chitosan 10% results in an increase in tensile strength of 11% and 14% in Young's modulus. Therefore, we could adjust the different mechanical properties simply by varying the mixing rate of the electrospun polymers. Using epithelial HepG2 cells, viability and kinetic cell adhesion assays were assessed to obtain biological evaluation. No cytotoxicity was observed and good cytocompatibility was confirmed. Functionalized nanofiber biomaterials with different MC/CS ratios substantiated significant bactericidal effectiveness against Gram-positive and Gram-negative bacterial culture strains. The novel functional electrospun wound dressing scaffold demonstrated effective and promising biomedical performance, healing both acute and chronic wounds.