Background <p>Total knee arthroplasty (TKA) has become a common surgical procedure for alleviating pain caused by end-stage osteoarthritis and improving joint dysfunction, but the optimal postoperative analgesic regimen remains controversial. This study aimed to evaluate the efficacy and safety of liposomal bupivacaine(LB) for peri-articular injection (PAI) in TKA, focusing on its impact on early postoperative outcomes, and comparing it with traditional ropivacaine hydrochloride (RH).</p> Methods <p>From February to June 2025, 121 patients undergoing total knee arthroplasty at Qingdao University Affiliated Hospital were enrolled. This single-center, parallel-group, double-blind study randomly assigned patients in a 1:1 ratio using a random number table to the LB or RH group. Prime outcomes include the visual analogue scale (VAS) within 72&#xa0;h after surgery and the consumption of opioid drugs. Secondary outcomes comprised postoperative knee range of motion (ROM), time to first ambulation (TFA), Timed Up-and-Go (TUG) test, 2-minute walk test(2MWT), length of hospital stay (LHT), and postoperative adverse events.</p> Results <p>Demographic and clinical characteristics were comparable between groups. The LB group demonstrated lower postoperative pain scores and opioid consumption. Additionally, LB group patients exhibited markedly greater joint range of motion and earlier time to first ambulation compared to the RH group. The incidence of adverse events was similar between groups. One patient in the LB group and two in the RH group experienced early postoperative complications, none of which were considered related to analgesic selection.</p> Conclusion <p>This study demonstrates that LB may alleviate postoperative knee pain, reduce the consumption of opioid drugs, and thereby facilitate recovery.</p> Trial registration <p>Clinicaltrials.gov. Identifier ChiCTR2400082998, 12/04/2024.</p>