Background <p>The prevalence of ankle fractures is increasing globally. Postoperative rehabilitation exercises constitutes an essential component of the surgical procedure. However, the severe pain in postoperative rehabilitation exercises remains a clinical problem. The objective of this study is to ascertain whether the administration of premixed nitrous oxide provides effective pain relief during the postoperative rehabilitation phase following the treatment of ankle fractures.</p> Methods <p>This study employed a single-center, randomized, double-blind controlled trial design. This study will enroll 100 patients. Patients undergoing rehabilitation exercises with acute pain (VAS ≥ 4) at least 1&#xa0;month after ankle open reduction and internal fixation will be eligible for inclusion. Patients will be assigned in a 1:1 ratio through a randomization process to an intervention group receiving a pre-prepared nitrous oxide/oxygen mixture or a control group receiving oxygen. Rehabilitation therapy will perform by a professional rehabilitation therapist. The primary outcome is pain score, and the secondary outcomes include anxiety score, physiological indicators, side events, satisfaction from patients and medical staffs, acceptance, and residual pain after rehabilitation.</p> Discussion <p>The study is an in-depth examination of the analgesic effect of nitrous oxide applied to postoperative rehabilitation exercises of ankle fracture. If this method proves to be successful, it could be widely applied to patients in postoperative rehabilitation exercises for ankle fracture, providing a new idea for pain management in the field of postoperative rehabilitation.</p> Trial registration <p>Chinese Clinical Trial Register ChiCTR2400089379. Registered on September 9, 2024. <a href="https://www.chictr.org.cn/showproj.html?proj=236994">https://www.chictr.org.cn/showproj.html?proj=236994</a></p>