Background <p>Against the backdrop of increasing attention to the mental health of medical students, this study aimed to investigate the network characteristics and core manifestations of loneliness and mental health among first-year medical students using network analysis, and to explore the impact of regulatory emotional self-efficacy (RESE) on this network.</p> Methods <p>A cross-sectional study examined 1,866 medical students using stratified cluster sampling. Loneliness, mental health, and RESE were assessed. We constructed two network structures of loneliness-mental health and loneliness-RESE-mental health. Additionally, we developed flow networks for negative and positive emotion regulation self-efficacy, incorporating depression and loneliness symptoms respectively, to demonstrate their interrelationships.</p> Results <p>The network of loneliness and mental health among first-year medical students was stable. “Seek help” and “Anxiety” were core manifestations, while “Isolation” and “Depression” were key bridge symptoms connecting loneliness and mental health. Expressing positive emotion regulation self-efficacy alleviated the impact of loneliness by promoting social interaction, whereas managing negative emotion self-efficacy reduced the negative effects of loneliness by decreasing feelings of left out. Unexpectedly, however, a positive correlation was observed between self-efficacy in expressing positive emotions and anxiety.</p> Conclusions <p>The network architecture linking loneliness and mental health among medical freshmen exhibits stability. Both expressing positive emotions and managing negative emotions self-efficacy demonstrate positive impacts on the loneliness and mental health of this particular group. These findings identify specific intervention targets for addressing mental health issues in medical freshmen and provide valuable evidence for developing tailored mental health promotion programs.</p> Clinical trial number <p>Not applicable.</p>