Nanofibrous polymeric scaffolds are considered special platforms for various biological applications such as drug delivery, tissue engineering, and wound healing. Three new fibrous nanocomposites of polyacrylonitrile (PAN) with Fe(III) metal-organic framework (Fe-MOF), namely, PAN/x%Fe-MOF (x = 5, 10, and 20), were fabricated using the electrospinning technique. SEM (scanning electron microscope), TEM (transmission electron microscope), BET (Brunauer-Emmett-Teller), EDS (energy dispersive X-ray spectroscopy) mapping, FTIR (Fourier-transform infrared), and PXRD (powder X-ray diffraction) were used to investigate the characteristics of the prepared compounds. The obtained results indicated that the Fe-MOFs were successfully enmeshed in the polymeric matrix. TEM and SEM images confirmed the fibrous structures. Our results from biological investigations concerning cell viability, cell proliferation, and biocompatibility demonstrated that PAN/5%Fe-MOF and PAN/10%Fe-MOF nanofibrous scaffolds with high porosity, cellular biocompatibility, optimum fiber diameter, and chemical stability had appropriate properties for cell attachment, proliferation, and spreading compared to pure PAN and PAN/20%Fe-MOF nanocomposites. In addition, cell viability of HUVECs (human umbilical vein endothelial cells) seeded on the nanocomposites was dependent on the Fe-MOFs present in the composites. Indeed, in vivo implantation results showed no inflammatory response and were associated with cell penetration. According to these results, PAN/5%Fe-MOF and PAN/10%Fe-MOF fibrous nanocomposites exhibited good biocompatibility without cytotoxic effects. The PAN/x%Fe-MOF nanocomposite scaffolds enhanced the biological reactions of the cells with their substrate. The prepared electrospun scaffolds have promising potential for biomedical applications such as tissue engineering investigations.