This study was aimed to investigate the therapeutic effectiveness of sericin in rats with monosodium iodoacetate (MIA)- induced knee osteoarthritis (KOA), focusing on evaluating its effectiveness via the TGF-β/Smad pathway. The KOA model was established through the injection of MIA into the knee joint, and the rats were randomly allocated into three groups: group 1 (control), group 2 (KOA control), and group 3 (KOA sericin). Sericin was administered intra-articularly to rats on days 1,7,14, and 21 (0.8 g/kg/mL, 50 µL). After 21 days, the rats were sacrificed, and serum samples were analyzed using the ELISA method to measure transforming growth faktör-Beta (TGF-β1), mother against decapentaplegic homolog 2 (Smad2), and connective tissue growth factor (CTGF) levels. Additionally, knee joint samples underwent histopathological evaluations with hematoxylin-eosin staining and immunohistochemical assessment using TGF-β1 and Smad2/3 antibodies. Serum TGF-β1 and CTGF levels were significantly increased in group 2 vs. group 1 (P < .05). A statistically significant decrease was observed in group 3 (P < .05). Serum Smad2 levels were not significantly different between groups. Histopathologically, group 2 showed a subchondral bone tissue, degeneration of the cartilage and deep fissures. On the other hand, group 3 showed reduced degeneration in chondrocyte cells, increased cartilage thickness, and a cartilage matrix that appeared close to normal were noted. Immunohistochemically, group 2 exhibited an increase in TGF-β1 and Smad expression, whereas group 3 decreased these expressions than group 2. Sericin demonstrates potential efficacy in the experimental KOA model in rats through the TGF-β1/Smad pathway. Consequently, sericin may emerge as a promising therapeutic agent for the treatment of KOA with further support from advanced clinical trials.