Mobile-bearing unicompartmental knee arthroplasty (UKA) is prone to rotational malalignment of the femoral component. Moreover, existing biomechanical studies frequently overlook the mechanical impact of patients’ bone quality on such surgical errors. To investigate the coupling effect of femoral component transverse rotation and bone quality on the biomechanical environment, a finite element model incorporating intact soft tissues was constructed. Based on bone mineral density variations, three models were established: normal bone (B1), osteopenia (B2), and osteoporosis (B3). Nine rotational conditions ranging from –14° to 14° in the transverse plane were simulated. Quantitative analysis revealed that external rotation significantly elevated the contact pressure on the polyethylene liner. Conversely, internal rotation (–14°) increased the lateral meniscus stress by approximately 16.8% compared to the neutral alignment (0°) via a “linkage mechanism”. Group B3 exhibited a pseudo “cushion effect”, wherein the peak strain of the tibial cancellous bone reached 5 883.9 με, exceeding the pathological threshold of 4 000 με; additionally, compared with Group B1, their average strain in the cortical bone increased by approximately 79.7%. In conclusion, transverse rotational malalignment of the femoral component serves as a direct mechanical trigger disrupting the biomechanical balance in UKA, and osteoporosis significantly amplifies this risk of failure. Therefore, for patients with compromised bone mass, strict neutral alignment must be pursued intraoperatively to circumvent cancellous bone microfractures and early prosthesis subsidence.