To illustrate the microstructural and histomorphological characteristics of osteophytes in the human knee osteoarthritis (OA). Tibial plateau specimens, including osteophytes and subchondral trabecular bone (STB) from weight-bearing and non-weight-bearing regions, were obtained from 81 patients with OA after total knee arthroplasty surgery. All the patients had varus deformity of the knee. Micro-CT was applied to evaluate the microstructure characteristics of the tibial plateau, which was segmented into 6 regions of interest (ROIs). After micro-CT scanning, decalcified and undecalcified bone histology were performed to assess histological features and bone remodeling status in these different ROIs. In both medial and lateral plateaus, osteophytes exhibited a less sclerotic microstructure and higher bone remodeling level compared with STB from weight-bearing and non-weight-bearing regions. Moreover, the medial osteophyte tended to have a more sclerotic microarchitecture and a relatively low level of bone metabolism than its lateral counterpart. Osteophyte, which consists of mesenchymal connective tissue cap, cartilage and mineralized bone tissue, demonstrated evident chondrocyte hypertrophy and endochondral ossification in the cartilage-to-bone interface. Compared with the non-weight-bearing region, the weight-bearing region showed more severely deteriorated cartilage, and more sclerotic subchondral bone with high remodeling status. Osteophytes exhibited a sparse microstructure and high bone remodeling level in knee OA, but demonstrating region-dependent variations. In addition, the microstructure, bone metabolism status and pathological alterations of osteochondral complex were distinct between weight-bearing and non-weight-bearing regions in the tibial plateau. Biomechanical stress might play a pivotal role in osteophyte formation and deterioration of osteochondral complex.