Objective. The aim of this study is to explore the safety and efficacy of single condylar knee prosthesis when treating knee single compartment osteoarthritis by measuring the decrease of hemoglobin, total postoperative blood loss, maximum reduction of HCT, and knee joint activity. Methods. A total of 80 patients with knee joint single compartment osteoarthritis treated in our hospital from January 2020 to December 2021 were studied. They were randomly assigned to a study group (n = 40) and a control group (n = 40). The study group was treated with total knee prosthesis, while the control group was treated with simple knee prosthesis. The decrease rate of hemoglobin, the amount of bleeding, and the maximum decrease of hematocrit were compared after treatment. The range of motion of knee joint was evaluated by the Fugl-Meyer motor function scale (FM-B) and Berg balance scale (BBS). Results. The decrease of hemoglobin in the study group at 24 hours, 36 hours, and 48 hours after treatment was remarkably lower ( P  < 0.05). The total blood loss and the maximum reduction of hematocrit(HCT) in the study group were lower ( P  < 0.05). The range of motion (ROM) of the knee joint in the study group at 6 and 12 months after treatment was remarkably higher than that before treatment and remarkably higher compared to the control group ( P  < 0.05). The FM-B scale and BBS scale of the studied cohort at 6 and 12 months after treatment were remarkably higher than those before treatment and were remarkably higher compared to the control’s ( P  < 0.05). Conclusion. The unicondylar knee prosthesis is safer and more effective in the treatment of noncompartmental osteoarthritis of the knee, facilitating less trauma and perioperative blood loss and enhancing the patient’s motion and balance.