BACKGROUND: Maternal psychological distress during pregnancy is associated with unfavorable outcomes in infants. Mindfulness-based interventions (MBIs) can effectively alleviate psychological distress, but there are often barriers to the access of face-to-face interventions. OBJECTIVE: This study aimed to investigate the effectiveness of a digital guided self-help (GSH) MBI (GSH-MBI) in reducing maternal psychological distress and improving infant neuropsychological performance. METHODS: This was a randomized controlled trial. We recruited 160 women who were 12 to 20 weeks pregnant and exhibited psychological distress. We randomized them into a digital GSH-MBI group and a control group (usual perinatal care). The digital GSH-MBI consisted of a 6-week intervention through a WeChat mini program, with a daily reminder sent to the participants by a research assistant via WeChat. The primary outcomes consisted of maternal psychological distress, including depression, anxiety, and pregnancy-related anxiety symptoms, which were assessed at 6 time points from baseline to 6 months post partum (only pregnancy-related anxiety symptoms were assessed 3 times during pregnancy). The secondary outcomes were infant neuropsychological outcomes, including temperament and developmental behaviors, which were assessed at 6 weeks and 6 months post partum. RESULTS: Compared with the control group, the digital GSH-MBI group showed a significant reduction in depression, anxiety, and pregnancy-related anxiety symptoms. In addition, the scores of the digital GSH-MBI group were lower than those of the control group for the 3 types of infant temperament at 6 weeks post partum, including quality of mood, distractibility, and adaptability. CONCLUSIONS: Digital GSH-MBIs are effective in alleviating psychological distress among pregnant women and protecting infant outcomes. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR2000040717; https://www.chictr.org.cn/showproj.aspx?proj=65376.