Injury-activated endogenous neural stem cells (NSCs) in the spinal cord have promising therapeutic applications for rebuilding the neuronal relays after spinal cord injury (SCI) because of their lack of immune-rejection following exogenous cell transplantation. However, these NSCs rarely differentiate into neurons and the damaged axonal regenerative ability is drastically reduced due to the adverse SCI microenvironment. Cetuximab, an EGFR signaling antagonist, has demonstrated the ability of promoting NSC differentiation into neurons. Taxol, in addition to stabilizing microtubules, has shown potential for enhancing axonal regeneration and reducing scar formation after SCI. In this study, we further verified the combined therapeutic effects of Cetuximab and Taxol on inhibition of scar deposition and promotion of neuronal differentiation, axonal outgrowth and functional recovery in a rat severe SCI model. A linear orderly collagen scaffold modified with Cetuximab and Taxol was grafted into the SCI site after the complete removal of 4 mm of spinal tissue. The results showed that the combined functional scaffold implantation significantly increased neural regeneration to reconnect the neural network. Moreover, scaffold transplantation decreases the deposition of varied scar-related inhibitors within the lesion center, further reflecting the need for a combination dedicated to increasing motor function following SCI. Collagen scaffold based-combined therapy provides a potential strategy for improving functional restoration of the injured spinal cord.