Background <p>Total hip arthroplasty (THA) is a common orthopedic surgery for elderly patients, but it is often associated with severe postoperative pain, leading to increased opioid consumption and delayed recovery. Against the backdrop of the increasing popularity of multimodal analgesia strategies, this study aimed to investigate the effects of preemptive intravenous administration of paracetamol-mannitol injection on postoperative analgesia, inflammatory response, and quality of recovery in elderly patients undergoing THA.</p> Methods <p>Sixty-six elderly patients scheduled for elective THA were randomly allocated using a random number table into either the experimental group (Group A, receiving paracetamol-mannitol injection 30&#xa0;min before surgery) or the control group (Group C, receiving an equal volume of normal saline). All patients received a sufentanil-based patient-controlled intravenous analgesia (PCIA) pump postoperatively. The primary endpoint was the Visual Analog Scale (VAS) score at rest 24&#xa0;h postoperatively. Secondary endpoints included cumulative 24-hour sufentanil consumption, time to the first analgesic request, number of effective PCIA demands, Brugge-mann Comfort Scale (BCS) scores, incidence of adverse reactions, and changes in serum levels of inflammatory markers (IL-1<i>β</i>, IL-6, TNF-<i>α</i>) and the neuro-stress protein S100<i>β</i>.</p> Results <p>All 66 enrolled patients completed the study with no dropouts. The baseline characteristics of the two groups were comparable. Compared to Group C, Group A exhibited significantly lower VAS scores at 6 and 24&#xa0;h postoperatively, a significant reduction in total 24-hour sufentanil consumption and the number of PCIA demands, and a significantly prolonged time to the first analgesic request (<i>P &lt;</i> 0.05). Furthermore, Group A exhibited significantly higher comfort scores at 6&#xa0;h postoperatively (<i>P &lt;</i> 0.05). At 24&#xa0;h postoperatively, there was a significant statistical difference in serum levels of the inflammatory marker TNF-<i>α</i> and the neuro-stress indicator S100<i>β</i> between the two groups (<i>P &lt;</i> 0.05). Moreover, within Group A, there was no significant statistical difference between preoperative and postoperative levels of TNF-<i>α</i> and S100<i>β</i> (<i>P &gt;</i> 0.05). There was no statistically significant difference in the incidence of postoperative adverse reactions between the two groups (<i>P &gt;</i> 0.05).</p> Conclusion <p>In elderly patients undergoing total hip arthroplasty, preemptive intravenous acetaminophen-mannitol effectively alleviates early postoperative pain, reduces opioid consumption, and enhances patient comfort, possibly by attenuating postoperative inflammation and neurostress responses to improve perioperative recovery; however, the clinical significance of associated changes in inflammatory and neurostress markers within 24&#xa0;h postoperatively remains to be further elucidated.</p> Trial registration <p>The trial was registered on Aug 6, 2025 in the Chinese Clinical Trial Registry(<a href="https://www.chictr.org.cn/bin/user">https://www.chictr.org.cn/bin/user</a> Project = 257710),registration number ChiCTR 2,500,107,208 (06/08/2025).</p>