Osteoarthritis (OA) is a serious joint disorder caused by degeneration of articular cartilage resulting in loss of mobility and reduction of gap between the bones. The present study investigated casticin for treatment of monosodium iodoacetate (MIA)-induced osteoarthritis (OA) in vivo. Casticin treatment at 1.25, 2.5, and 5 mg/kg doses significantly (p < 0.05) prevented MIA-induced reduction in weight bearing distribution between left and right limbs compared to the untreated group. In casticin treated rats a significant (p < 0.05) reduction in MIA-mediated increase in interleukin (IL)-1 beta, IL-6 and tumor necrosis factor (TNF)-alpha levels was observed in the serum. Treatment with 5 mg/kg casticin reduced inflammatory cytokine production in MIA administered rat serum comparable to that of the control group. Treatment with 1.25, 2.5, and 5 mg/kg doses of casticin caused a significant (p < 0.05) reduction in MIA-mediated up-regulation of IL-1 beta, IL-6 and cyclooxygenase-2 (COX-2) mRNA in rat knee joints. Casticin treatment of the rats at 1.25, 2.5, and 5 mg/kg doses effectively alleviated the MIA-induced elevation in matrix metalloproteinase (MMP)-2, and MMP-9 mRNA level. Treatment with 1.25, 2.5, and 5 mg/kg doses of casticin significantly (p < 0.05) prevented MIA-induced knee tissue damage. Therefore, casticin prevents subchondral bone deterioration in OA rats via targeting inflammatory processes.