Due to the emotional impact of COVID-19 on university students, the goal was to explore the relationship between anxiety, depression, psychological well-being, and life satisfaction among pre-professional interns. The research was carried out using an explanatory cross-sectional design, with the participation of 1011 pre-professional interns of 13 health networks from the department of Puno (Peru). Data were collected using the Satisfaction with Life Scale, Generalized Anxiety Disorder Scale-2, Patient Health Questionnaire 2, and the Psychological Wellbeing Scale. The main data analysis was carried out using the R statistical software, and implementing the confirmatory factor analysis technique, which evidenced that the explanatory model provides an acceptable value. Based on the above, a negative relationship between depression and life satisfaction, (β = -.60, p.001) and a positive relationship between anxiety and life satisfaction (β = .28, p.001) was shown, in addition to a mediating effect of the psychological wellbeing related to depression and life satisfaction (p.001). In conclusion, life satisfaction is explained concerning the degree of depression and anxiety, as well as the moderating effect of psychological well-being. Despite that, there is an urgent need to take preventive actions to strengthen the mental health of the pre-professional health interns, who have also been providing support during the COVID-19 pandemic.