Objective: To explore the relationship between loneliness, self-efficacy, and satisfaction with life of Left-behind middle school students in China. Methods: A cluster random sampling method was used to study students from Left-behind middle schools in Binhai County of Jiangsu Province. The loneliness scale, general self-efficacy scale, and satisfaction with life scale were used to conduct questionnaire surveys. Results: Compared with non-left behind middle school students, Left-behind middle school students had higher loneliness, lower self-efficacy, and satisfaction with life. There were significant gender differences in loneliness and satisfaction with life of the two types of students. Whether to live in school or not had an insignificant impact on the loneliness and satisfaction with life of Left-behind middle school students. Loneliness had a significant negative predictive effect on the satisfaction with Left-behind middle school students' life and self-efficacy. In predicting satisfaction with life by loneliness, self-efficacy generally played a part of the mediating role, which could partially buffer the adverse effects of loneliness on student satisfaction with life. Conclusion: The mental health of left-behind middle school students should arouse the common concern of family, school and society. Try to do some intervention counseling in reducing the experience of loneliness and enhancing the sense of self-efficacy to improve their satisfaction with life and maintain a positive mental state.