Purpose <p>Opioid-propofol sedation is standard for gastrointestinal endoscopy but may contribute to postoperative fatigue (POF). This study compared the severity of POF between sufentanil-propofol and alfentanil-propofol sedation in patients undergoing gastrointestinal endoscopy.</p> Methods <p>In this randomized trial, 248 patients scheduled for esophagogastroduodenoscopy and/or colonoscopy received either alfentanil (7.5–10&#xa0;μg/kg) or sufentanil (0.1–0.2&#xa0;μg/kg) combined with propofol for deep sedation. The primary outcome was POF severity assessed by the Christensen Fatigue Scale (CFS) 30&#xa0;min post-procedure. Secondary outcomes included recovery times (awakening and ambulation), incidence of clinically significant fatigue (CFS ≥ 6), and adverse events.</p> Results <p>At 30&#xa0;min post-procedure, the alfentanil group had significantly lower CFS scores than the sufentanil group (mean [standard deviation, SD]: 4.7 [1.0] vs. 5.7 [1.0]; mean difference –1.1, 95% CI –1.3 to –0.8; <i>P</i> &lt; 0.001). The proportion of patients with CFS score ≥ 6 was also lower in the alfentanil group (20.8% vs. 35.7%, <i>P</i> = 0.004). Recovery was faster in the alfentanil group for both awakening (3.0 [2.2] vs. 5.5 [2.8] minutes, <i>P</i> &lt; 0.001) and ambulation (12.8 [2.4] vs. 15.7 [3.4] minutes, <i>P</i> &lt; 0.001). Adverse events including dizziness, nausea, and vomiting were less frequent with alfentanil (15.2% vs. 26.0%, <i>P</i> = 0.035; and 4.8% vs. 12.2%, <i>P</i> = 0.036).</p> Conclusions <p>Compared to sufentanil, alfentanil combined with propofol significantly reduced postoperative fatigue and enhanced recovery in patients undergoing deeply sedated gastrointestinal endoscopy.</p> Registration <p>Name of trial registry: Chinese Clinical Trial Registry. Registration number: ChiCTR2300071429. URL: <a href="https://www.chictr.org.cn/showproj.html?proj=186791">https://www.chictr.org.cn/showproj.html?proj=186791</a></p>