The aim of this study was to investigate the effects of sinomenine (SIN) on cartilage degeneration and synovial macrophage polarization in knee osteoarthritis (KOA) rats and its potential mechanism. In the experiment, 50 SD rats were randomly divided into five groups (n = 10): control group (Ctrl), KOA group, low-dose SIN group (SIN-L), high-dose SIN group (SIN-H) and SIN-H + coumermycin A1 group (SIN-H + CA1). The KOA model was constructed by injecting sodium iodoacetate into the knee joint cavity, and then a series of tests were carried out. The pathological changes of synovial membrane and cartilage in rats were observed by histological staining. The levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-4 and IL-10 in peripheral serum were detected by ELISA. The level of polarization markers of synovial macrophages was determined by immunofluorescence staining. Western blot was used to detect the expression levels of proteins related to the tyrosine protein kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. The experimental results showed that compared with the Ctrl group, the Mankin's and OARSI scores, IL-6 and TNF-α levels, CD86/F4/80 fluorescence intensity ratio, p-JAK2/JAK2 and p-STAT3/STAT3 expression levels of cartilage in the KOA group were significantly increased (P<0.05). The thickness of cartilage and synovium, the levels of IL-4 and IL-10, and the ratio of CD206/F4/80 fluorescence intensity were significantly decreased (P<0.05). Compared with KOA group, Mankin's and OARSI scores, IL-6 and TNF-α levels, CD86/F4/80 fluorescence intensity ratio, p-JAK2/JAK2 and p-STAT3/STAT3 expression levels in cartilage of SIN-L group and SIN-H group were significantly decreased (P<0.05). The thickness of cartilage and synovium, the levels of IL-4 and IL-10, and the ratio of CD206/F4/80 fluorescence intensity were significantly increased in a dose-dependent manner (P<0.05). Compared with SIN-H group, Mankin's and OARSI scores, IL-6 and TNF-α levels, CD86/F4/80 fluorescence intensity ratio, p-JAK2/JAK2 and p-STAT3/STAT3 expression levels in cartilage of SIN-H + CA1 group were significantly increased (P<0.05). The thickness of cartilage and synovium, the levels of IL-4 and IL-10, and the ratio of CD206/F4/80 fluorescence intensity were significantly decreased (P<0.05). It can be seen that SIN can significantly reduce the degeneration of knee cartilage in KOA rats and promote the polarization of synovial macrophages to M2 type. The mechanism may be related to the inhibition of JAK2/STAT3 pathway activation.