Medical education is highly demanding and evidence shows that medical students are three times more susceptible to deteriorating physical and mental health than the average college student. While trait anxiety may further increase such risk, little is known about the role of trait mindfulness in mitigating these effects. Here we examine the protective role of specific mindfulness facets as mediators in pathways from trait anxiety to perceived stress, psychosomatic burden and sleep-wake quality in medical students, across repeated measurements throughout the first trimester of the school year. Preclinical medical students enrolled in the second year of the Medical School of University of Bologna completed self-report questionnaires examining personality traits as well as physical and psychological wellbeing. Data were collected at the beginning (Time 1: N = 349) and the end of the first trimester (Time 2: N = 305). As students approached the end of the trimester and upcoming exams, reported levels of perceived stress, psychosomatic problems and difficulties in wakefulness increased significantly compared to the beginning of the trimester. Mediation results showed that trait anxiety predicted such outcomes whereas the protective role of mindfulness facets in mitigating these effects was significant only at Time 2. Specific facets of Nonjudging of inner experience and Acting with awareness proved to be the most effective mediators. Findings highlight that the beneficial role of mindfulness facets in mitigating negative consequences of trait anxiety on medical student wellbeing is revealed in high-pressure periods and when self-regulation is needed the most. Cultivating awareness and nonjudgmental acceptance of one’s inner experiences is a crucial self-regulation resource that can help medical students sustain their wellbeing as they learn and throughout their high-pressure education and professional careers.