Oxidative stress is critically attributed for impeding tissue repair and regeneration process. Elimination of over-accumulated, deleterious reactive oxygen species (ROS) could be elicited to accelerate healing in tissue engineering applications. Antioxidant biomolecules play a pivotal role in attenuating oxidative stress by neutralizing the free radical effects. Herein, we describe the synthesis and fabrication of novel quinone-based chromenopyrazole (QCP) antioxidant-laden silk fibroin (SF) electrospun nanofiber scaffold (QCP-SF) for tissue engineering applications. The spectral characterization of the synthesized compounds (6a-6h) were analysed by using NMR, FTIR and mass spectra and cell viability study of all the synthesized compounds were evaluated by MTT assay in primary rat bone marrow stem cells (rBMSCs). Among the prepared molecules, compound 6h showed an excellent cell viability, and antioxidant efficacy of compound 6h (QCP) was investigated through 1,1‑diphenyl‑2‑picrylhydiazyl (DPPH) scavenging assay. QCP expressed high antioxidant activity with IC50% of DPPH scavenging was observed about 5.506 ± 0.2786 μg. Novel QCP laden SF fiber scaffolds (QCP-SF) were characterized and incorporation of QCP did not affect the nanofiber architecture of QCP-SF scaffold. QCP-SF scaffold exhibited an enhanced thermal and mechanical stability when compared to native SF fiber mat. In vitro biocompatibility studies were evaluated using NIH 3T3 fibroblasts and rBMSCs. The QCP-SF scaffold displayed an increased cell attachment and proliferation in both cell types. In vitro wound healing study (scratch assay) of QCP-SF scaffold showed an excellent cell migration with NIH 3T3 cells into scratch area and complete cell migration occurred within 24 h. Based on results, we propose that QCP-loaded SF (QCP-SF) nanofibrous scaffolds can serve as a promising potential antioxidant fibrous scaffold for skin tissue engineering applications.