In knee osteoarthritis (OA) patients, a focal cartilage defect is commonly found, especially in the medial compartment. In addition, cartilage softening is often observed at the defect rim. Both factors may alter the loading distribution and thereby the contact pressures, previously related to cartilage degeneration. To determine contact pressure in-vivo during motion, computational modelling can be used. The aim of this study was to analyse knee cartilage pressures during walking in healthy and damaged cartilage using a multi-scale modelling approach. Using 3D motion capture and musculoskeletal models, multi-body simulations of the stance phase of gait calculated knee kinematics and muscle, ligament and contact forces. These were subsequently imposed to a finite element (FE) model including tibial and femoral bones and cartilage. FE analyses were performed using intact cartilage as well as including a medial tibial cartilage defect, with and without softening of the defect rim. Specifically during loading response, a medial cartilage defect reduced the contact surface (−28%) and thereby increased the contact pressure (+33%) compared to intact cartilage, particularly on the medial compartment (+75% in contact pressure). Including softening of the cartilage rim increased the contact area (+22%) and decreased contact pressures (−9%) compared to the defect. This indicates that a focal defect increases the cartilage loading. This is partially compensated by softening of the cartilage rim. Therefore, the role of focal defects in altered cartilage loading and consequent OA development always needs to be discussed acknowledging the cartilage status at the defect rim.