Several studies have indicated that pain peaks at 24 to 48 hours after total knee arthroplasty (TKA) surgery. TKA has been associated with disruption in normal sleep patterns, swelling knee, and significant blood loss. However, a satisfactory regime to resolve these mentioned problems has yet to be found.In this study, a total of 420 patients were randomly allocated into two groups and treated with continuous irrigation of either 4000 mL cold saline with 0.5% epinephrine or normal temperature solution. Clinical outcomes including pain scores at rest during postoperative three days, drainage output, analgesic consumption, decreased hemoglobin, sleep quality, and satisfaction rate were analyzed. Mean scores and postoperative change in scores were calculated.Visual analog scale (VAS) pain scores in the treatment group were significantly reduced from 4 hours (P = 0.0016) to 24 hours (P = 0.0004) after TKA. Additional benefits including reduced analgesic consumption, improved satisfaction rate, and sleep quality were observed. In addition, a significant reduction in blood loss reflected by decreased Hb and drainage was found.In this study, irrigation with a cold 0.5% epinephrine solution was a beneficial and cost-effective treatment that decreased acute postoperative VAS pain scores immediately after and 1 day after surgery. Patients reported postoperative improvement in sleep quality and overall satisfaction rate with a decrease in morphine usage. In addition, a reduction of intraoperative blood loss might decrease the blood transfusion rate and related costs. Collectively, irrigation with cold 0.5% epinephrine offers a safe, simple, and effective treatment that might improve recovery and enhance quality of life of patients undergoing TKA.