Patients with advanced cancer often have bone metastases, causing bone destruction and cancer-induced bone pain (CIBP). The CCAAT/enhancer binding protein β (c/EBPβ) mediated the regulation of various pro-inflammatory molecules in microglia. To investigate the specific effect and regulatory mechanism of c/EBPβ in CIBP, a mice model of Lewis lung cancer (LLC) cells implantation was constructed. Our data demonstrated that the c/EBPβ was remarkably elevated in the spinal cord of CIBP mice. Specific knocking down c/EBPβ relieved the mechanical allodynia and thermal hyperalgesia of CIBP mice by suppressing the microglia activation and pro-inflammatory cytokines generation. Besides, overexpressing c/EBPβ could prompt severe pain behaviors with spinal neuroinflammation in naïve mice. Notably, the upstream regulator constitutive photomorphogenic 1 (COP1) was gradually reduced in the spinal cord of CIBP mice. Upregulating the expression of COP1 effectively alleviated the nociceptive behaviors of CIBP mice by inhibiting the accumulation of c/EBPβ and subsequent neuroinflammation. However, knocking down COP1 caused the rapid increase of c/EBPβ and exacerbation of spinal neuroinflammation, ultimately leading to behavioral damage in naïve mice. In conclusion, the absence of COP1 promoted the accumulation of c/EBPβ and neuroinflammatory molecules in the spinal cord of CIBP mice, which extends the future therapeutic approach for CIBP.