Diabetes presents significant health risks, including diabetic foot ulcers, which can lead to amputation or death if left untreated. It has been acknowledged that hypoxia-inducible factor-1 alpha (HIF-1α) dysfunction in diabetic wounds delays healing and tissue repair. This study explores the therapeutic potential of roxadustat (ROX), a novel HIF-1α stabilizer, within an optimized electrospun gelatin/silk fibroin nanofibrous dressing (ROX-NF). The dressing's properties were optimized using a 22 full factorial design, with varied gelatin (GN) and silk fibroin (SF) amounts as factors and responses including degradation, porosity, swelling, drug release, and drug content percentages. In vitro characterization of the optimized ROX-NF showed a degradation rate of 90.24 ± 1.29 %, porosity of 84.41 ± 3.04 %, cumulative drug release of 93.13 ± 3.05 % over 48 h, and a high drug content of 99.12 ± 0.02 %, with structural analyses confirming successful ROX integration within the nanofibrous matrix. Additionally, in vivo evaluation of the optimized ROX-NF in diabetic rat models demonstrated accelerated wound closure, achieving 5.17 ± 1.2 % wound area by day 14 compared to 19.3 ± 2.8 % with ROX dispersion. Histological analysis revealed enhanced collagen deposition, neovascularization, and organized epidermal and dermal layers. Furthermore, PCR, ELISA, and Western blot assays demonstrated a marked upregulation of key wound healing markers, including HIF-1α, TGF-β, VEGF, and collagen I, in the ROX-NF group relative to ROX dispersion. These findings underscore the efficacy of combining ROX with nanofiber characteristics, offering a promising approach for diabetic wound management through accelerated wound closure and enhanced tissue regeneration.