Objective To observe the effect of Kanggusuiyan tablets on serum cytokines in rabbits with chronic osteomyelitis (COL). Methods Rabbits received an injection of Staphylococcus aureus intramedullarly in right tibias to induce an experimental model of COL before being divided into five groups using the random number table method: sham, model, positive control (clindamycin60 mg/kg), Kanggusuiyan tablet high and low dose (480 and 240 mg/kg) groups. Animals were orally administrated for six weeks. On the 2nd, 4th and 6th week after administration, the right tibias of rabbits were examined by X-ray and their severity was graded, while the erythrocyte sedimentation rate (ESR) and white blood cells (WBCs) were calculated. The expressions of procalcitonin (PCT), C-reactive protein (CRP), interleukin-1β (IL-1β), IL-4, IL-6 and IL-10 in sera were measured by enzyme-linked immunosorbent assay. Results The severity of the right tibia in Kanggusuiyan tablet groups (480 mg/kg on the 2nd, 4th and 6th week and 240 mg/kg on the 4th and 6th week, respectively) was markedly attenuated compared to the model group (P<0.05 or P<0.01). In comparison with the model group, levels of ESR, WBC, PCT and CRP in Kanggusuiyan tablet groups were significantly reduced on the 2nd, 4th and 6th week, respectively (P<0.05 or P<0.01). Compared to the model group, the serum levels of IL-1β and IL-6 in Kanggusuiyan tablet groups were markedly decreased on the 2nd, 4th and 6th week, respectively (P<0.05 or P<0.01), while the expressions of IL-4 and IL-10 were markedly increased on the 6th week (P<0.01). Conclusions Kanggusuiyan tablets could protect against COL in rabbits. The mechanism likely involves the modulation of proinflammatory/anti-inflammatory cytokine balance and improvement of inflammatory responses.