The primary role of muscles is to move, and control joints. It is therefore important to understand how degenerative joint disease changes this role with the resulting effect on mechanical joint loading. Muscular control strategies can vary depending on strength and coordination which in turn influences joint control and loading. The purpose of this study was to investigate the variation in neuromuscular control mechanisms and joint biomechanics for three subject groups including those with: uni-compartmental knee osteoarthritis (OA), listed for high tibial osteotomy surgery (pre-HTO, n = 10); multi-compartmental knee OA listed for total knee replacement (pre-TKR, n = 9), and non-pathological knees (NP, n = 11). Lower limb kinematics and electromyography (EMG) data for subjects walking at self-selected speed, were input to an EMG-driven musculoskeletal knee model which was scaled and calibrated to each individual to estimate muscle forces. Compared to NP, the peak gastrocnemius muscle force reduced by 30% and 18% for pre-HTO and pre-TKR respectively, and the peak force estimated for hamstring muscle increased by 25% for pre-HTO. Higher quadriceps and hamstring forces suggest that co-contraction with the gastrocnemius could lead to higher joint contact forces. Combined with the excessive loading due to a high external knee adduction moment this may exacerbate joint destruction. An increased lateral muscle co-contraction reflects the progression from NP to uni-compartmental OA (pre-HTO). Pre-TKR patients adopt a different gait pattern to pre-HTO patients. Increased medial muscle co-activation could potentially differentiate between uni- or multi-compartmental OA.