For patients suffering from traumatic brain injury (TBI), the closure of dural defects after decompressive craniectomy is the prerequisite to restoring normal physiological functions. It is also an urgent challenge to provide a neuroprotection effect against the primary and secondary nerve damage during long-term recovery. To solve these issues, we herein develop a class of bioactive, nanofibrous dural substitutes that can long-term release insulin-like growth factor 1 (IGF-1) for improving the survival and neurite outgrowth of neural cells after TBI. Such dural substitutes were polycaprolactone (PCL) nanofibers encapsulated with hyaluronic acid methacryloyl (HAMA)/IGF-1 by blend or coaxial electrospinning techniques, achieving bioactive PCL/HAMA/IGF nanofibrous dural substitutes with different release profiles of IGF-1. The nanofibrous dural substitutes exhibited good mechanical properties and hydrophobicity, which prevent cerebrospinal fluid leakage, maintain normal intracranial pressure, and avoid external impact on the brain. We also found that the viability and neurite outgrowth of SH-SY5Y cells and primary neurons were significantly enhanced after neurite transection or oxygen and glucose deprivation treatment. Taken together, such PCL/HAMA/IGF nanofibrous dural substitutes hold promising potential to provide neuroprotection effects after primary and secondary nerve damage in TBI, which would bring significant benefits to the field of neurosurgery involving the use of artificial dura mater.