OBJECTIVES: This study aimed to evaluate the efficacy of combining multimodal cocktail drug local injection with adductor canal block versus adductor canal block alone for postoperative pain management following anterior cruciate ligament (ACL) reconstruction with hamstring autograft. METHODS: A randomized controlled trial was conducted with 40 patients undergoing ACL reconstruction. Participants were assigned to two groups: one received a multimodal cocktail drug injection into the peri-articular and peri-hamstring regions combined with an adductor canal block (study group), while the other received only the adductor canal block (control group). Pain was assessed using the numeric rating scale (NRS) overall and at the posteromedial thigh. Additional data included morphine consumption, postoperative nausea and vomiting (PONV), knee range of motion, and patient-reported outcomes. Statistical comparisons were performed using the unpaired t-test or Mann-Whitney U test, as appropriate, with significance set at P <
0.05. RESULTS: The multimodal cocktail group reported statistically significantly lower overall NRS pain scores at 6, 12, and 24 hours postoperatively compared to the control group (P <
0.001 for all). At the posteromedial thigh, NRS scores were statistically significantly lower at 6 and 12 hours (P <
0.001) but not at 24 hours or later time points. Morphine consumption was statistically significantly lower in the multimodal cocktail group at 12 and 24 hours (P = 0.004 and P = 0.008, respectively), and PONV scores were reduced (P = 0.04). No statistically significant differences were observed between the groups in knee flexion (P = 0.656) or patient-reported outcomes at 6 weeks (P >
0.05). CONCLUSIONS: The findings of this study suggest that multimodal cocktail injections may enhance early postoperative pain control, reduce opioid consumption, and minimize PONV without compromising short-term functional recovery. These findings support its potential role in pain management following ACL reconstruction, though larger studies are warranted to confirm these results. LEVEL OF EVIDENCE: Level I - randomized controlled trial.