Background <p>Esketamine exerts analgesic effects and has pharmacological properties of bronchodilation and elevation of mean arterial pressure, making it an interesting analgesic agent for patients with ARDS. Therefore, we conducted a randomized controlled trial comparing the effects of esketamine/midazolam and remifentanil/midazolam on respiratory mechanics and oxygenation in mechanically ventilated patients with ARDS.</p> Methods <p>In this prospective, randomized, controlled study, patients with ARDS who were undergoing mechanical ventilation were randomly assigned to receive either remifentanil/midazolam (<i>n</i> = 25) or esketamine/midazolam (<i>n</i> = 25). Both groups maintained equivalent levels of sedation and analgesia. The primary outcomes were airway resistance (R_aw) and static respiratory system compliance (C_st) at 24, 48, and 72&#xa0;h post-medication administration. Plateau Pressure (P_plat), peak airway pressure (P_peak), hemodynamic parameters, mechanical ventilation duration, and ICU length of stay were also recorded.</p> Results <p>C_st at 72&#xa0;h post-medication in esketamine group (49.8 ± 13.8) was higher than that in control group (42.4 ± 11.9) (<i>P</i> &lt; 0.05). There was no significant difference in R_aw at 24&#xa0;h, 48&#xa0;h and 72&#xa0;h post-medication between the two groups (<i>P</i> &gt; 0.05). At 72&#xa0;h post-medication, both P_plat and P_peak in the esketamine group [(15.6 ± 3.1); (25.7 ± 3.8)] were significantly lower than those in the control group[(17.7 ± 4.2); (28.5 ± 4.7)] (<i>P</i> &lt; 0.05). Additionally, the esketamine group [(256.6 ± 89.1); (266.4 ± 88.4); (284.92 ± 84.45)] demonstrated significantly higher PaO₂/FiO₂ ratios compared to the control group [(208.7 ± 61.5);(219.52 ± 61.28); (222.00 ± 68.54)] at all measured time points (<i>P</i> &lt; 0.05). MAP and heart rate were higher in the esketamine group than in the control group, while cumulative doses of vasoactive drugs were comparatively lower in the esketamine group. The duration of mechanical ventilation and ICU length of stay did not-differ (<i>P</i> &gt; 0.05).</p> Conclusion <p>Esketamine/midazolam leads to improved in C_st and PaO₂/FiO₂ ratio compared to remifentanil/midazolam in mechanically ventilated patients with ARDS.</p> Clinical trial registration <p>This study was registered at Chinese Clinical Trial Registry (ChiCTR2300070733) on April 21, 2023. URL: <a href="https://www.chictr.org.cn/">https://www.chictr.org.cn/</a>.</p>