In the present study, the temozolomide (TMZ) loaded poly (ε-caprolactonediol) based polyurethane (PCL-Diol-b-PU) nanofibers were fabricated as local delivery systems against glioblastoma. The structure and morphology of nanofibers were characterized using FTIR and SEM analysis. The gold nanoparticles were coated on the nanofibers surface to enhance the efficacy of nanofibers for local chemotherapy of brain tumors. The effect of various ratios of DMF/THF solvents and solution concentration on the morphology and fiber diameter of PCL-Diol-b-PU nanofibers was investigated. The small burst release of TMZ with sustained TMZ release from both PCL-Diol-b-PU and gold-coated PCL-Diol-b-PU nanofibers were achieved over 30 days. The Korsmayer-Peppas kinetic and Fickian diffusion models were used to describe the mechanism of TMZ release from nanofibers. The in vitro cell viability results revealed that the higher antitumor activity of synthesized nanofibers against glioblastoma cells compared with pristine TMZ. It was concluded that the prepared nanofibrous implants showed a higher potential in the local chemotherapy of brain tumors.