Background Music therapy has been used as a complementary intervention to provide synergistic analgesia for various procedures. Objective To evaluate the effects of natural sound therapy on pain intensity and agitation scores in intubated adult Chinese patients who received endotracheal suctioning in a critical care unit. Methods A prospective, real-world, randomized, double-blind, controlled study was conducted from July 2021 through February 2022 among intubated surgical intensive care unit patients in a Chinese hospital. Patients were randomly assigned to a control group receiving conventional treatment or an intervention group receiving natural sound therapy plus conventional treatment (50 patients in each group). Patients’ pain intensity and agitation levels were analyzed before, during, immediately after, 5 minutes after, and 15 minutes after completion of endotracheal suctioning. Pain intensity was assessed with the Critical-Care Pain Observation Tool (CPOT); agitation was assessed with the Richmond Agitation-Sedation Scale (RASS). Results According to CPOT scores, patients in the intervention group had significant relief of pain intensity during, immediately after, and 5 minutes after endotracheal suctioning compared with patients in the control group (all P < .001). The RASS scores showed that agitation levels were significant lower in the intervention group than in the control group during (P = .002) and immediately after (P < .001) endotracheal suctioning. Conclusions In this real-world study, natural sound therapy was part of a holistic bundle of interventions used to reduce pain and agitation in surgical intensive care unit patients during endotracheal suctioning.