Background: Multimodal postoperative pain regimens are widely used following total knee arthroplasty (TKA). However, there are few studies on the rehabilitation of the co-application of local infiltration analgesia (LIA) and femoral nerve block (FNB) combined with dexmedetomidine (DEX) for patients undergoing TKA. This study aimed to investigate the effect of LIA plus FNB and co-application of perioperative DEX on TKA outcomes. Methods: 95 patients were randomized into two groups. Patients in group B (n = 48) received a single preoperative FNB and LIA. Patients in group A (n = 47) received FNB and LIA, as well as continuous intravenous injection of DEX starting from the induction of anesthesia to postoperative day 2. All patients were allowed patient-controlled analgesia postoperatively. Visual analog scale (VAS) scores, knee range of motion (ROM) degrees, narcotic consumption, length of hospital stay (LOS), complications, Hospital for Special Surgery (HSS) scores and Montreal Cognitive Assessment-Basic (MoCA-B) Scores were recorded. Results: In group A, the mean VAS scores at rest and during movement were lower, the amount of rescue analgesia was decreased, first time of ambulation was reduced, ROM was improved, MoCA-B Scores were increased, LOS was shorter, HSS scores were higher postoperatively compared with group B (all p < 0.05). Conclusion: Our study indicated multimodal analgesia involving a single FNB and LIA combined with DEX accelerates rehabilitation for patients undergoing TKA.