There is a growing body of research that shows a significant association between mindfulness and mental health. However, studies on Saudi populations are still in their infancy. Mindfulness is a personal tendency to focus on the present time in a non-judgmental manner, including the interior and exterior experience of feelings and events. The first aim of this study is to examine the relationship between mindfulness, stress, depression, and academic performance in a sample of medical students from King Saud University. The second aim is to explore the potential moderation effects of mindfulness on the impact of stress on academic performance and depression in the study population. This cross-sectional study examined 289 medical students who were selected by a stratified random sampling technique and completed validated online questionnaires measuring mindfulness, stress, and depression. The data were analyzed using SAS version 9.2, and R software was used for graphs. Correlation analysis showed that mindfulness is inversely associated with depression and stress, but not with academic performance. Furthermore, multiple logistic regression showed that mindfulness can predict both depression and stress. We also found that two subscales of mindfulness can moderate the relation between stress and depression: non-judging of inner experience and describing. The findings suggest that a higher mindfulness score is associated with lower depression and stress levels and could buffer against depression in a stressful environment. There is a need for further research to investigate the relation of mindfulness with positive psychological outcomes, as well as experimental trials to examine the efficacy of mindfulness training on improving mental wellbeing in our community.