Wear particle-induced osteolysis is the main reason for the long-term failure of total knee replacement. Simulator testing is the standard procedure for validating wear performance pre-clinically. The load and kinematics specified in the International Organization for Standardization (ISO) are standard input profiles for wear testing of implants. Directions of internal–external (IE) rotation and anterior–posterior (AP) translation have been modified in the new version of ISO 14243-3 2014. This study focused on investigating the effects of internal–external rotation and anterior–posterior translation on the wear of knee implants. Numerical wear prediction was performed using the finite element model along with two wear models, namely the contact pressure independent model and contact pressure dependent model. Addition of internal–external rotation significantly increased the wear, and the two wear models obtained similar results. The effect of internal–external rotation direction on wear was slight. Forward movement of the tibial insert during flexion decreased the wear under the contact pressure independent model and increased the wear under the contact pressure dependent model. When the AP direction switched, the two models obtained opposite wear tendencies. The results predicted by the contact pressure dependent model were consistent with those of wear tendency experiments reported in the literature. Further investigation of wear physical principles was necessary to gain a more reliable model. This study demonstrated that both internal–external rotation and anterior–posterior translation were pivotal factors influencing the contact mechanism and wear of total knee implants. More realistic kinematics are necessary for accurate wear assessment.