Objective: Stress is a significant concern in medical education, and identifying effective ways to deal with stress may help with students’ mental health and professional development. This study aimed to examine the effects of the Transforming Stress Program (TSP) amongst first-year medical students on their stress mindset and coping strategies when confronted with stressors. Methods: We conducted a quasi-experimental study at the University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam. A total of 409 first-year students at the Faculty of Medicine were divided into intervention group (205 students) and control group (204 students). The 10-week TSP was delivered as an extra-curricular course. The training adopts psychoeducation based on Dialectical Behavioral Therapy with mindfulness as a fundamental practice incorporated into each component of the program. The intervention group received the training in the first semester; the control group received identical program in the second semester. Stress Mindset Measurement and Brief Coping Orientation to Problems Experienced were measured before the intervention (T0), immediately after intervention on Intervention group (T1), and six months after intervention on Intervention group (T2). Results: At T1, the intervention group showed 65% improvements in stress mindset scores and increases in coping strategies scores in six domains (Problem solving, Social support, Humor, Religion, Venting, and Self-distraction) and decreases in three (Avoidance, Substance use, and Self-blame). The effect sizes were significant in all outcomes (Cohen’s d > 0.2). Measurements of the control group did not change significantly in the same period. At T2, effects of the TSP were found decreased in some domains (Avoidance, Substance use, and Self-blame) compared to T1, but largely remained significantly better than T0. Conclusions: The TSP is a feasible and effective approach that significantly enhanced medical students’ stress mindset and coping strategies. Some effects were still observable 6 months after the intervention. The relatively intensive intervention requires support of the school administration and staff.