Three hundred fifty-six adult patients undergoing total knee arthroplasty were randomized to receive a continuous intraoperative infusion of S-ketamine (n = 178) or placebo (n = 178). The primary outcome of interest was the incidence of rebound pain (RP) within 12 hours post-surgery. Secondary outcomes of interest included the incidence of RP within 24 hours, time to RP onset, time to first rescue analgesia, pain scores during rest and activity, opioid consumption, recovery quality, and patient satisfaction. Outcomes were assessed up to 3 days postoperatively. Overall, the results of the study revealed that S-ketamine significantly reduced the incidence of RP at 12 hours, delayed its onset, and improved recovery and satisfaction metrics. These findings suggest that S-ketamine is effective in reducing early postoperative RP and enhancing recovery following knee arthroplasty.