The COVID-19 pandemic clearly has various detrimental psychological effects on people’s mental health, emphasizing the importance of mindfulness in overcoming such repercussions. This is in line with the growing number of studies that have been conducted to assess the effects of mindfulness in diverse settings. However, the role of mindfulness in reducing mental health issues among university students has received little attention. Therefore, the current work seeks to investigate how mindfulness could reduce the anxiety, depression, and stress of university students and how self-compassion and psychological well-being could mediate the links between mindfulness and these mental health disorders. To that end, an explanatory sequential mixed-method design was adopted. Quantitative data collected, through a two-wave survey, from 560 Vietnamese students having an average age of 18.7 years were used to test the hypotheses. To measure the six variables in the research models, we opted for the Five Facet Mindfulness Questionnaire (FFMQ), Self-Compassion Scale (SCS-26), Depression Anxiety Stress Scale (DASS-21–7 items for each subscale), and World Health Organization-Five Well-Being Index (WHO-5). Additionally, qualitative data from 19 in-depth interviews were utilized to explain the quantitative findings and explore students’ experiences in practicing mindfulness and self-compassion to decrease stress, depression, and anxiety. The results elucidated that self-compassion and psychological well-being serially mediated the relationships between mindfulness (as a predictor) and anxiety, stress, and depression (as outcome variables). The findings demonstrated the key role of mindfulness in increasing students’ self-compassion and psychological well-being as well as reducing anxiety, depression, and stress. This research holds substantial contributions by providing universities and psychotherapists with recommendations to deal with negative psychological consequences caused by COVID-19.