In recent years with regard to the development of nanotechnology and neural stem cell discovery, the combinatorial therapeutic strategies of neural progenitor cells and appropriate biomaterials have raised the hope for brain regeneration following neurological disorders. This study aimed to explore the proliferation and neurogenic effect of PLGA and PLGA-PEG nanofibers on human SH-SY5Y cells in in vitro condition. Nanofibers of PLGA and PLGA-PEG biomaterials were synthesized and fabricated using electrospinning method. Physicochemical features were examined using HNMR, FT-IR, and water contact angle assays. Ultrastructural morphology, the orientation of nanofibers, cell distribution and attachment were visualized by SEM imaging. Cell survival and proliferation rate were measured. Differentiation capacity was monitored by immunofluorescence staining of Map-2. HNMR, FT-IR assays confirmed the integration of PEG to PLGA backbone. Water contact angel assay showed increasing surface hydrophilicity in PLGA-PEG biomaterial compared to the PLGA substrate. SEM analysis revealed the reduction of PLGA-PEG nanofibers' diameter compared to the PLGA group. Cell attachment was observed in both groups while PLGA-PEG had a superior effect in the promotion of survival rate compared to other groups (p < .05). Compared to the PLGA group, PLGA-PEG increased the number of Ki67 cells (p < .01). PLGA-PEG biomaterial induced neural maturation by increasing protein Map-2 compared to the PLGA scaffold in a three-dimensional culture system. According to our data, structural modification of PLGA with PEG could enhance orientated differentiation and the dynamic growth of neural cells.