Background: Psychological distress is a growing problem among medical students worldwide. This highlights the need for psychological interventions to focus on mental health and improve well-being in this population. Objective: This study developed an internet-based, self-help, acceptance and commitment therapy program (iACT 2.0), aiming to examine its effectiveness in reducing depression, anxiety, stress, psychological inflexibility (PI), and obsessive-compulsive symptoms (OCSs) among medical students. Methods: A total of 520 Chinese postgraduate medical students were randomly assigned to either an iACT 2.0 intervention group (n=260; six online lessons, once every 5 days) or a control condition (n=260; without intervention). Participants completed questionnaires including the 21-item Depression Anxiety Stress Scale, the revised Obsessive-Compulsive Inventory, and the Multidimensional Psychological Flexibility Inventory at the preintervention (T1), postintervention (T2), and 1-month follow-up time points (T3). No therapist support was provided during the 1-month iACT 2.0 intervention period. Data were collected via an online platform and analyzed using repeated-measures ANOVA. Results: Participants in the intervention group demonstrated a significant decrease in depression, anxiety, stress, PI, and OCSs compared to the control group after the intervention (F=22.9-672.04, all P<.001). Specifically, the intervention group showed significant reductions in all measured outcomes from the preintervention to postintervention time point and at the 1-month follow-up (all P<.001). In contrast, no significant changes were observed in the control group over the same period (all P>.05). The groups did not differ significantly at baseline (all P>.05). Significant differences were noted at both the postintervention and follow-up time points (all P<.001). Conclusions: This study demonstrated that the newly developed iACT 2.0 was effective in reducing depression, anxiety, stress, PI, and OCSs. Notably, the positive effects of the intervention persisted at the 1-month follow-up. This program can offer a useful addition to existing mental illness treatment and lead to improvements in clinical and psychotherapy planning while simultaneously reducing the burden on traditional counseling and services. Trial Registration: Chinese Clinical Trial Registry ChiCTR2300070725; https://tinyurl.com/2h75wx8n
