Background: Enhanced recovery following total knee arthroplasty (TKA) has been advocated to enhance postoperative recovery. Multimodal cocktail periarticular injection (MCPI) use for pain control in TKA has gained wide acceptance. MCPI-containing corticosteroids are believed to be an effective solution owing to their local anti-inflammatory effects and ability to reduce the local stress response postoperatively. However, there is conflicting evidence regarding its benefits. This trial aims to compare MCPI with a high dose of corticosteroid, normal dose of corticosteroid, and non-corticosteroid during TKA, to assess the effectiveness of MCPI containing corticosteroids in postoperative pain relief, functional improvement, rescue analgesia, and side effects and provide evidence that high-dose corticosteroids result in prolonged pain control and better recovery following TKA. Methods: This is a double-blinded, randomized, placebo-controlled study. A total of 234 patients scheduled for TKA will be recruited. During surgery, before wound closure, 80 ml of the cocktail analgesic will be injected into the muscle and joint capsule for local infiltration analgesia; the participants will be randomly assigned to three groups to receive a high dose of betamethasone MCPI (group H), normal dose of betamethasone MCPI (group N), and non-betamethasone MCPI (group C). The following indices will be recorded and analyzed: the strongest knee pain experienced during 90 degrees flexion at 6 h, 24 h, 48 h, 72 h, 5 days, 14 days, and 30 days after surgery; 1 min walking ability; and circumference around the patella at 2, 5, 14, and 30 days after surgery; Knee Society knee score at 14 days and 30 days after surgery; C-reactive protein and blood sedimentation; blood sugar 2, 5, 14, and 30 days following surgery; rescue analgesic consumption; and adverse events. If any participant withdraws from the trial, an intention-to-treat analysis will be performed. Discussion: The results of this study will provide clinical evidence on the effectiveness of MCPI-containing corticosteroids in postoperative pain relief, functional improvement, rescue analgesia, and adverse events, as well as provide evidence on the efficacy of high-dose corticosteroids in prolonged pain control and better recovery following TKA.