Wnt signaling are recognized key factors in neuronal development, cell proliferation and axonal guidance. However, RAGE effect on wnt signaling after spinal cord injury (SCI) are poorly understood. Our study aims to explore RAGE blockade effect on wnt signaling after SCI. We constructed Allen SCI model and micro-injected with RAGE neutralizing antibody or IgG after injury. We determined β-catenin, wnt3a and its receptor frizzled-5 via Western blot. We determined β-catenin/NeuN expression at 2 weeks after SCI via immunofluorescence (IF). We found that β-catenin, wnt3a and wnt receptor frizzled5 expression were activated after SCI at 3 days after injury. However, RAGE blockade inhibit β-catenin, wnt3a and frizzled5 expression. We found that β-catenin accumulation in NeuN cells were activated after SCI via IF, however, RAGE blockade reduced β-catenin and NeuN positive cells. RAGE blockade attenuated number of survived neurons and decreased area of spared white matter around the epicenter. RAGE signaling may involved in disrupting wnt signaling to aids neuronal recovery after SCI.