Objective To establish osteoarthritis model of the knee joint in mice on the basis of knocking out SIRT1 gene and to observe the differences in the morphology of the cartilage tissue using single staining and compound staining. Methods The knee joint specimens were divided into two groups:SIRT1^-/- control group (group A, n=6) and SIRT1^-/- osteoarthritis model group (group B, n=6). The knee anterior cruciate ligament was traversed, and the ipsilateral medial meniscus was cut to establish an osteoarthritis model of knee joint. HE staining, safranin O-fast green staining, safranin O-alcian blue staining, safranin O staining, fast green staining, alcian blue staining were used to observe the morphological changes in the articular cartilage of the knee. Results Safranin O-fast green staining and safranin O-alcian blue staining showed better results in observation of the morphology of chondrocytes, the structure of cartilage layers, the presence of type Ⅱ collagen, tide line and the changes of subchondral bone. While the safranin O staining and alcian blue staining had certain advantages in the observation of the defects of cartilage tissue. Conclusions Compared with the single staining, the compound staining used in this study have obvious advantages in obtaining useful information of the cartilage structure in the observation of morphology of cartilage tissues in SIRT1 gene knock-out mice.