Background: Public health emergencies may lead to severe psychological stress, especially for healthcare workers, including frontline healthcare workers and public health workers. However, few stress management interventions have been implemented for healthcare workers even though they require more comprehensive interventions than the general public. Self-Help Plus (SH+) is a novel psychological self-help intervention developed by the World Health Organization. It is accessible, scalable, and cost-effective and has the potential to be quickly applied to help people cope with stress and adversity. The major objective of this study is to evaluate the effectiveness of SH+ interventions on the alleviation of stress levels and mental health problems among healthcare workers. Methods: A randomized controlled trial of SH+ will be conducted to investigate the stress level and mental health status of Chinese healthcare workers and control subjects in Guangzhou. Assessments will be performed before (baseline), at the end of (1 month), and 2 months after (3 months) the intervention. After completing the baseline screening questionnaire, eligible participants will be randomly assigned to one of the two groups in a 1:1 ratio by block randomization. During the 1-month intervention period, the intervention group will receive the SH+ intervention and the control group will receive information about mental health promotion. The intervention will be delivered by the research assistant via social media platforms. The primary outcome is the level of stress, which will be measured by a 10-item Perceived Stress Scale. Secondary outcomes including mental health symptoms will also be collected. Discussion: Given the potential for multiple COVID-19 waves and other infectious disease pandemics in the future, we expect that SH+ will be an effective stress management intervention for healthcare workers. The findings from this study will facilitate the application of SH+, and the trial is expected to be extended to a larger population in the future.