Sodium alginate (SA) approved its high potential in tissue engineering and regenerative medicine. One of the main weaknesses of this polysaccharide is its low spinnability which nanofiber based scaffolds are the interest of scientists in biomedical engineering. The main aim of this study was to improve the spinnability of SA in combination with polyvinyl alcohol (PVA). It was also tried to optimize the main parameters in electrospinning of the optimized SA;PVA ratio including voltage, flow rate, and working space. To aim this, Response surface methodology under central composite design was employed to design the experiments scientifically. The final nanofiber scaffolds were studied using scanning electron microscopy, Fourier transform infrared spectroscopy, degradability, swelling, tensile strength, porosity, nanofiber diameter, contact angle, and cytotoxicity. Based on the results, the best ratio for SA:PVA was 1:6.5. The solution with this concentration was spinnable in various values for the process parameters. The fabricated scaffolds under these conditions revealed good physical, chemical, mechanical, and biological features. L929 cell lines revealed high viability during 48 h of culture. The results revealed the uniform and homogeneous nanofibers with the regular size distribution (166 nm) were obtained at 30 kV, 0.55 µl/h, and 12.5 cm. To sum up, the optimized ratio under the reported conditions can be a good biologically compatible candidate for skin tissue engineering.