Cancer‐induced bone pain (CIBP) profoundly influences patients' quality of life. Exploring the mechanisms by which CIBP occurs is essential for developing efficacious therapies. Various studies have shown that proinflammatory factors were involved in CIBP. SET domain containing lysine methyltransferase 7/9 (SET7/9) may modulate the expression of NF‐κB‐dependent proinflammatory genes in vitro. However, whether SET7/9 may participate in the maintenance of CIBP remains unknown. In this study, NCTC 2472 cells were inoculated into the intramedullary space of the femur to establish a mouse model of CIBP. Upregulation of spinal SET7/9 expression was related to pain behaviours in tumour‐inoculated mice. Intrathecal cyproheptadine (10 or 20 nmol) attenuated response to painful stimuli in a dose‐dependent manner. Moreover, there was a concomitant decrease in spinal SET7/9 and RANTES expression. The antinociceptive effects of cyproheptadine were abolished by pre‐intrathecal administration of SET 7/9 (0.2 μg) for 30 minutes before intrathecal cyproheptadine (20 nmol) administration. These results indicated that spinal SET7/9 may contribute to the maintenance of CIBP in mice. Hence, targeting of spinal SET7/9 might be a useful alternative therapy for the treatment of CIBP.