Clinically, Microtubule-targeted agents–induced neuropathic pain hampers chemotherapeutics for patients with cancer. Here, we found that application of paclitaxel or vincristine increased the protein and mRNA expression of CXCL12 and frequency and amplitude of miniature excitatory post synaptic currents (mEPSCs) in spinal dorsal horn neurons. Spinal local application of CXCL12 induced the long-term potentiation of nociceptive synaptic transmission and increased the amplitude of mEPSCs. Inhibition of CXCL12 using the transgenic mice (CXCL12−/+) or neutralizing antibody or siRNA ameliorated the mEPSC's enhancement and mechanical allodynia. In addition, paclitaxel and vincristine both could increase the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the acetylation of histone H4 in the CXCL12-expressing neurons. Immunoprecipitation and chromatin immunoprecipitation assays demonstrated that antitubulin chemotherapeutics increased the binding of STAT3 to the CXCL12 gene promoter and the interaction between STAT3 and p300, and contributed to the enhanced transcription of CXCL12 by increasing the acetylation of histone H4 in CXCL12 gene promoter. Inhibition of STAT3 by intrathecal injection of adeno-associated virus encoding Cre and green fluorescent protein into STAT3flox/flox mice or inhibitor S3I-201 into rats suppressed the CXCL12 upsurge by decreasing the acetylation of histone H4. Finally, blockade of CXCR4 but not CXCR7 ameliorated the paclitaxel- or vincristine-induced mechanical allodynia. Together, these results suggested that enhanced interaction between STAT3 and p300 mediated the epigenetic upregulation of CXCL12 in dorsal horn neurons, which contributed to the antitubulin chemotherapeutics–induced persistent pain.