Depression is an important factor that endangers human psychological and physical health. It is found that depression or "depressive symptoms" that do not meet the diagnostic criteria mainly occur in late adolescence. College students are in the critical period of transition from adolescence to adulthood, and they are easily prone to mood swings, which is a high incidence of depression. The detection rate of "depressive symptoms" was 29.3% in 2002 and 48.24% in 2020, while the detection rate was only 5%-8% in the general population. It indicates that the current situation of college students' depression is pessimistic. It is necessary to strengthen the research on college students' depression to provide theoretical support for the prevention of depression and the promotion of college students' mental health. Studies have found that loneliness has significant correlation with depression and psychological inflexibility. Mindfulness, as a positive emotion regulation ability, can effectively alleviate depression. In this study, SPSS25.0 was used to conduct descriptive analysis, correlation analysis. Mplus8.3 was used for Common Method Variance (CMV)analysis, Confirmatory Factor Analysis(CFA), and bias-corrected Bootstrap method was used to analysis the mediating effect and moderated effect. Firstly, we conducted a preliminary analysis which consists of four parts: a) CFA was utilized to confirm the construct validity; b)Verified that reliability and validity were up to standards; c) Descriptive statistics and bivariate correlations were presented; d) CMV analysis were used to rule out method variance. Secondly, the mediating effect of cognitive failure was conducted. More importantly, latent moderated structural equation was adopted to test the moderated effect. Finally, the interactions were depicted using the high (1 SD above the mean) and low (1 SD below the mean) scores to analyze the moderated effect of anxiety. Objective: In order to explore the relationship between loneliness and depression and the role of psychological rigidity and mindfulness. Methods: 504 college students (male=131, female=373) were investigated with University of California Los Angeles, Psychological Inflexibility scale, Self-Rating Depression Scale and Mindful Attention Awareness Scale. The structural equation model based on latent Moderated Structural Equation was used to explore the role of mindfulness in it. Results: (1)The Combined Reliability(CR) and Average Variance Extracted(AVE) amount of all scales reached the standard, and the fitting indexes of CFA were good. (2) CMV was not significant; (3) There were a significant positive correlation between loneliness, psychological inflexibility and depression；mindfulness and loneliness, psychological inflexibility and depression were significantly negative correlation; (4) Loneliness had negative prediction of depression, and the loneliness can influence depression through psychological inflexibility; (5) Mindfulness can moderate the relationship between loneliness and depression: Compared to low individuals with lower mindfulness, those with higher mindfulness were less likely to be affected by the negative impact of loneliness. Conclusion: Loneliness affects depression through psychological inflexibility, and mindfulness moderate the direct path. These indicate that mindfulness intervention can be enhanced in the future, which can not only improve the college students’ mental health level, but also explore the applicability of mindfulness cognitive therapy in college students, which is conducive to the promotion of positive psychology and mindfulness cognitive therapy.