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Background To explore the relationship between loneliness and social avoidance of college students, the mediating role of depression and interpersonal trust between them, and the regulating role of self-esteem. A theoretical approach to provide an internal mechanism for the intervention of loneliness and social avoidance. Methods We included 1050 college students using simple random cluster sampling with the self-esteem scale(SES), the social avoidance and distress scale(SAD) , UCLA loneliness scale, the interpersonal trust scale(ITS), and the self-rating depression scale(SDS). And descriptive statistical analysis and correlation analysis, structural equation model analysis were conducted Results (1) The correlations between depression, loneliness, interpersonal trust, self-esteem and social avoidance were all statistically significant. (2) There is a significant positive correlation between loneliness and social avoidance. (3) Depression and interpersonal trust play multiple mediating roles between loneliness and social avoidance. (4) Self-esteem plays a regulating role between interpersonal trust and social avoidance. Conclusion Loneliness has a significant positive predictive effect on social avoidance. More profound loneliness among college students correlates with social avoidance.It provides a new way to explain the mechanism of loneliness, and a new perspective for the clinical intervention of loneliness, that is, from the perspective of their self-experience and self-esteem.