During the COVID-19 pandemic, health care professionals experienced high levels of depression. However, extant research has not highlighted effective internet-based psychological interventions to improve the mental health in this population during the pandemic. It remains unclear whether self-guided, internet-based cognitive behavioral therapy (iCBT) programs are effective in improving the mental health of health care workers during the COVID-19 pandemic. The aim of this study was to evaluate the effectiveness of a smartphone-based iCBT stress management program for reducing the depression experienced by nurses in Vietnam and Thailand. From March to April 2022, a 2-arm, parallel-group randomized controlled trial was implemented. One arm offered a 7-week self-guided iCBT program, and the other offered treatment as usual as a control arm. Full-time nurses were recruited from 6 hospitals: 2 hospitals in Vietnam and 4 hospitals in Thailand. The primary outcome of this program was the severity of depression measured by the Depression Anxiety Stress Scale-21 items. Follow-up surveys were conducted to measure the change in depression severity at 3 months (July-August 2022) and at 6 months (October-November 2022) after baseline. Mixed modeling for repeated measures was used to test the effects of the intervention compared with the control for the follow-up. A total of 1203 nurses were included in this study: 602 in the intervention group and 601 in the control group. The follow-up rate at 3 and 6 months ranged from 85.7% (515/601) to 87.5% (527/602). The completion rate for the program was 68.1% (410/602). The group difference in depression was significant at the 3-month follow-up (coefficient=-0.92, 95% CI -1.66 to -0.18; P=.02) and nonsignificant at the 6-month follow-up (coefficient=-0.33, 95% CI -1.11 to 0.45; P=.41). The estimated effect sizes were -0.15 and -0.06 at the 3- and 6-month follow-ups, respectively. Our study shows that the smartphone-based iCBT program was effective in reducing depression at the 3-month follow-up among hospital nurses in Vietnam and Thailand during the COVID-19 pandemic. However, the effect size was small, and therefore, these results may not be clinically meaningful. UMIN Clinical Trials Registry UMIN000044145; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000050128. RR2-10.20944/preprints202303.0450.v1.