AIM: To investigate the impact of oxycodone on gastrointestinal function in patients with moderate to severe acute respiratory distress syndrome undergoing mechanical ventilation. METHODS: Fifty patients with moderate to severe ARDS caused by severe pneumonia admitted to the Intensive Care Department of Fuling Hospital, Chongqing University from January 2022 to June 2023 were selected for the study. The patients were randomly divided into a remifentanil group (n=25) and a hydroxycodone group (n=25). They were treated with remifentanil and hydroxycodone for pain relief. We observed the incidence and severity grading of acute gastrointestinal injury (AGI), clinical outcomes (length of mechanical ventilation, ICU length of stay, and mortality at day 90), gastric emptying indicators (GRV, GER, MI), nutritional status (ALB, PAB), respiratory and circulatory indicators (Cst, OI, PaCO2, VIS). RESULTS: The occurrence of AGI showed no notable disparity between the remifentanil and oxycodone groups (96% vs. 72%, P=0.289), yet the remifentanil group exhibited a more severe AGI rating compared to the oxycodone group (P=0.009). The oxycodone groups GRV at 48 and 72 hours post-treatment was less than the remifentanil groups, with the MI surpassing the remifentanil groups (P<0.05), and the GRE exhibited comparable alterations (P>0.05). Post-treatment, the oxycodone groups ALB and PAB levels were elevated (P<0.05), whereas the remifentanil groups pre-treatment and post-treatment PAB remained unchanged (P>0.05), and the oxycodone groups PAB exceeded the remifentanil groups (P=0.035). However, the ALB, PAB, and ALB levels before and post-treatment were almost identical in both groups (P>0.05). Additionally, there was no significant variance in clinical and respiratory outcomes between the two patient groups (P>0.05). CONCLUSION: Hydroxycodone has a smaller inhibitory effect on gastric emptying in patients with moderate to severe acute respiratory distress syndrome undergoing mechanical ventilation, and has a milder degree of acute gastrointestinal injury. It can also improve the nutritional status of patients and has reliable safety. Hydroxycodone may be more beneficial in protecting the gastrointestinal function of patients with acute respiratory distress syndrome.