Severe spinal cord injury (SCI) always leads to permanent sensory and motor dysfunction. However, the therapeutic effects of current treatment methods, including high dose methylprednisolone, surgical interventions and rehabilitative care, are far from satisfactory. In recent years, cellular, molecular, tissue engineering and rehabilitative training have shown promising results in animal models. Poly-ε-caprolacton (PCL) – based hydrogel composite system has been considered as a promising strategy to direct the axon growth and mimic the properties of natural extracellular matrix. In this study, we found the addition of the fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF) to the hydrogel induces the production of axon growth-supportive substrates. The addition of the glial-derived neurotrophic factor (GDNF) to the hydrogel further induces axon directional growth. This “five-in-one” composite scaffold, referred to as PCL/PEG/FGF2/EGF/GDNF, improved the locomotor function in rats 8 weeks after spinal cord injury (SCI) after implantation in transected spinal cord. Furthermore, histological assessment indicated that the designed composite scaffold guided the neuronal regeneration and promoted the production of axon growth-supportive substrates, providing a favorable biological microenvironment. Our novel composite scaffold provides a promising therapeutic method for SCI.