Toll‐like receptors (TLRs) are a family of molecules that play a critical role in innate immunity. TLRs can be activated by heat shock proteins (HSPs), necrotic cells, extracellular matrix, and oxidized lipids – all of which are found in the injured spinal cord. Here, using a model of spinal cord injury, we show dramatic induction of TLRs and molecules associated with TLR signaling. The injury was produced by extradural compression of the spinal cord using an aneurysm clip with a closing force of 24 g to the dura via a four‐level T5‐T8 laminectomy in mice. Our present data show that the deficiency of TLR4 in C57BL/10ScN mice (TLR4 knockout) significantly impairs the normal progression of SCI/repair and functional recovery compared with wild type (WT) animals. We evaluated the following points: histological damage, motor recovery, nuclear Factor‐κB expression, cytokines production, inducible nitric oxide synthase (iNOS) expression, neutrophil infiltration, glial fibrillary acidic protein (GFAP) and CD11β expression, nitrotyrosine and poly‐ADP‐ribose (PAR) formation, glial cell‐derived neurotrophic factor (GDNF) expression, apoptosis (Caspase 3, Bax and Bcl‐2 expression). Capable of both protective and pathological roles, TLR4 can be helpful or harmful under varying neurological conditions. When and why TLR4 initiates beneficial outcome is still largely unknown, but progress in the field suggests that this question will receive much attention, as TLR4 is a useful and druggable target.