Background <p>In high-altitude environments with hypobaric hypoxia, chronic hypoxia can affect organs. This study aimed to determine whether high-flow nasal oxygen (HFNO) can reduce the incidence of hypoxemia in elderly patients undergoing gastroscopy with sedation at high altitudes.</p> Methods <p>This single-center, partially-blinded, prospective randomized trial was conducted in Shigatse, Tibet, China (3800&#xa0;m above sea level). Elderly patients aged ≥ 60 undergoing gastroscopy with sedation were randomly assigned to either the HFNO group (60&#xa0;L per minute, 100% oxygen) or the conventional nasal cannula (CNC) group (6&#xa0;L per minute). The primary endpoint was the incidence of hypoxemia, defined as pulse SpO₂ &lt; 90% for &gt; 10&#xa0;s during sedation.</p> Results <p>The incidence of hypoxemia was significantly lower in the HFNO group than the CNC group (2.8% vs. 32.9%, risk ratio (RR): 0.691; 95% confidence interval (CI): 0.584–0.818, <i>p</i> &lt; 0.001). The median SpO₂ after pre-oxygenation was similar between the groups (97.0% [96.0–98.0] vs. 96.0% [95.0–98.0], <i>p</i> = 0.053). However, the median minimum SpO₂ during the procedure was significantly higher in the HFNO group compared to the CNC group (96% [95–98] vs. 93% [87–96], <i>p</i> &lt; 0.001). The median duration of hypoxemia and the number of hypoxemia episodes were 0.0&#xa0;s (0.0–22.0) and 0 (0–1), respectively. In contrast, the values were 0.0&#xa0;s (0.0–0.0) and 0 (0–0) in the HFNO group (<i>p</i> &lt; 0.001). The median recovery time was shorter in the HFNO group compared to the CNC group (1.0&#xa0;min [0.5–1.5] vs. 1.5&#xa0;min [1.0-2.5], <i>p</i> = 0.003).</p> Conclusions <p>Compared to CNC, HFNO significantly reduced the incidence of hypoxemia during gastroscopy with sedation in elderly patients at high altitudes.</p> Trial registration <p>ChiCTR2400085110; registered on 31 May 2024.</p>