Background: With ever-increasing demand for total knee arthroplasty (TKA), most healthcare systems around the world are concerned about its socioeconomic burden. Most centers have universally adopted well-defined clinical care pathways to minimize adverse outcomes, maximize volume, and limit costs. However, there are no prospective comparative trials reporting benefits of these risk mitigation (RM) strategies. Methods: This is a prospective cohort study comparing post-TKA 90-day complications between patients undergoing RM before surgery and those following a standard protocol (SP). In the RM group, we used a 20-point checklist to screen for modifiable risk factors and evaluate the need for optimizing non-modifiable comorbidities. Only when optimization goals were achieved, patients were offered TKA. Results: TKA was performed in 811 patients in the SP group and in 829 in the RM group, 40% of which were simultaneous bilateral TKA. In both groups, hypertension was the most prevalent comorbidity (48%), followed by diabetes (20%). A total of 43 (5.3%) procedure-related complications were seen over the 90-day postoperative period in the SP group, which was significantly greater than 26 (3.1%) seen in the RM group (p = 0.039). The commonest complication was pulmonary thromboembolic, 6 in each group. Blood transfusion rate was higher in the SP group (6%) than in the RM group (< 1%). Conclusions Screening and RM can reduce 90-day complications in patients undergoing TKA.