The aim of the study was to longitudinally investigate symptomatic and structural factors prior to total knee replacement (TKR) surgery in order to identify influential factors that can predict a patient’s need for TKR surgery. In total, 165 participants (60% females; 64.5 ± 8.4 years; 29.7 ± 4.7 kg/m2) receiving a TKR in any of both knees within a four-year period were analyzed. Radiographic change, knee pain, knee function and quality of life were annually assessed prior to the TKR procedure. Self-learning artificial neural networks were applied to identify driving factors for the surgical procedure. Significant worsening of radiographic structural change was observed prior to TKR (p ≤ 0.0046), whereas knee symptoms (pain, function, quality of life) worsened significantly only in the year prior to the TKR procedure. By using our prediction model, we were able to predict correctly 80% of the classified individuals to undergo TKR surgery with a positive predictive value of 84% and a negative predictive value of 73%. Our prediction model offers the opportunity to assess a patient’s need for TKR surgery two years in advance based on easily available patient data and could therefore be used in a primary care setting.