(1) Background: The purpose of this study was to determine whether preemptive duloxetine in patients with central sensitization (CS) is effective for acute postoperative pain control and wound healing following total knee arthroplasty (TKA). (2) Methods: CS was defined as a score of 40 points or higher on the Central Sensitization Inventory (CSI) survey. Thirty-nine patients with CS were randomly assigned to either the duloxetine group ( = 19) or the placebo group ( = 20). The duloxetine group took duloxetine 30 mg once a day, while the placebo group took the placebo medication once a day. A pain visual analog scale (VAS) and the Brief Pain Inventory (BPI), wound complications, the temperature of the surgical site, and adverse events were investigated. Skin temperature was measured at the center of the patella using a portable digital thermometer. (3) Results: The duloxetine group reported significantly lower pain VAS scores during follow-up periods up to 6 weeks after surgery (all < 0.05). BPI interference also showed significantly superior results in the duloxetine group after surgery (all < 0.05). Although there was no difference in the rate of wound complications between the two groups ( > 0.05), the duloxetine group showed significantly lower wound temperature than the placebo group during the follow-up period (all < 0.05). (4) Conclusion: In this study, preemptive duloxetine effectively reduced pain and lowered wound temperature following TKA in CS patients.