Medical students experience high levels of psychological stress during clinical training. However, most medical curricula do not teach self-care skills. The COVID-19 pandemic has disrupted medical education causing increased distress among students. To report the implementation and impact of an eight-week multifaceted mindfulness-based self-care program on medical students’ distress and well-being during the COVID-19 pandemic. One hundred twenty-three fourth-year medical students attended the program as part of a mandatory course from April to May 2020, during the rising phase of COVID-19 in Chile. They were evaluated using validated tests before and immediately after the program. The measures included burnout, dispositional mindfulness, perceived stress, traumatic stress reactions, general well-being, resilience, and stress coping strategies. Burnout prevalence decreased from 44% to 24%, whereas students with high dispositional mindfulness increased from 25% to 44%. Burnout reduction was mostly due to decreased emotional exhaustion. Additionally, students reported lower levels of stress, self-blaming, and traumatic stress reactions alongside an increased use of active coping strategies and resilience levels after the program. A formal educational intervention, teaching self-awareness and self-regulation skills can help reduce medical students’ distress and promote their well-being even amidst a pandemic.