This study was aimed at investigating the effects of platelet-rich plasma (PRP) and low-intensity pulsed ultrasound (LIPUS) on the joint friction parameters and biomechanical properties of articular cartilage in a non-traumatic knee osteoarthritis (OA) model. Fifty adult male Dunkin Hartley guinea pigs were randomly divided into five groups: control, OA60, OA + US, OA + PRP and OA + US + PRP). Non-traumatic knee OA was induced with a single dose of 3 mg of mono-iodoacetate (MIA) by intra-articular injection. Intra-articular PRP was injected twice in the OA + PRP and OA + US + PRP groups. LIPUS was delivered in 10 sessions in the OA + US and OA + US + PRP groups. By use of the pendulum free oscillation test, joint friction (coefficient of friction) was measured. In addition, the instantaneous elastic modulus and aggregate modulus were measured using the stress-relaxation test. MIA injection decreased cartilage thickness, instantaneous elastic modulus and aggregate modulus, and increased joint friction. The friction coefficients in the OA + US and OA + US + PRP groups reached near-normal values, and there was no significant difference compared with the control group (p = 0.232 and p = 0.459, respectively). The instantaneous elastic modulus and aggregate modulus in the OA + US group increased significantly compared with the OA + PRP group (p < 0.05). It seems that both LIPUS and PRP injection effectively improved joint lubrication, but LIPUS was superior to PRP in improving the mechanical properties of the articular cartilage.