Background and purpose: Outpatient nursing is an occupation with high emotional labor and job stress. The purpose of this study was to examine the effects of auricular acupressure on stress, anxiety, and depression of outpatient nurses. Materials and methods: The study design was a randomized controlled trial. Participants were 54 outpatient nurses, divided into an experimental (n = 28) and a control group (n = 26). Auricular acupressure using vaccaria seeds was administered to the experimental group, while placebo auricular acupressure using vaccaria seeds was administered to the placebo group. Sessions continued for 5 weeks. Outcome measurements included blood tests such as cortisol and serotonin. Results: There was a statistically significant difference in depression scores (t = 3.111, p = 0.002) and serotonin levels (t = 6.304, p < 0.001) between the experimental and placebo groups. Auricular acupressure decreased depression scores, and the depression-related physiological index, serotonin, also changed significantly. Conclusion: Auricular acupressure using vaccaria seeds was effective in decreasing depression in outpatient nurses.