Specific protein 1 (Sp1) is a member of the Sp/Kruppel-like factor family, which regulates cellular processes of neurons in the nervous system. This study was performed to examine the regulatory role and the underlying mechanism of transcription factor Sp1 in neuropathic pain (NP)-like behaviors after spinal nerve ligation (SNL). Sp1 and histone deacetylase 1(HDAC1) expressions were determined in the C57BL6 mouse model with NP-like behaviors after SNL, which demonstrated that Sp1 and HDAC1 elevation occurred in neurons in the spinal dorsal horn of SNL mice. The chromatin immunoprecipitation assay verified that Sp1 was bound to the HDAC1 promoter region and HDAC1 to the SRY-box-containing gene 10 (SOX10) promoter region in the spinal dorsal horn. Immunofluorescence was performed to determine Sp1, HDAC1, and SOX10 in the spinal dorsal horn neurons as well as the neuronal marker (NeuN), microglial marker (Iba-1), and astrocyte marker (GFAP). The nociceptive test was performed to characterize the hindlimb paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of mice 0-10 days after model establishment. Loss- and gain-of-function assays revealed that Sp1 promoted HDAC1 expression, and HDAC1 in turn promoted SOX10 expression. HDAC1 elevation reversed the effects of Sp1 silencing, and the increased PWT and PWL of SNL mice were negated after SOX10 overexpression. Meanwhile, SOX10 also restored the results by Sp1 knockdown. Collectively, downregulating Sp1 alleviates NP-like behaviors after SNL via the HDAC1/SOX10 axis.