Many studies have shown that mobile phone dependence decreases subjective well-being, but there have been relatively few studies that investigate the specific mechanisms between mobile phone dependence and subjective well-being. In this study, the mediating effect of self-esteem and the moderating effect of social support were investigated to explore the specific mechanisms between mobile phone dependence and subjective well-being. The objective of the study is to explore the mechanism of mobile dependence on subjective well-being by constructing a moderated mediation model. College students from twenty classes in three universities were randomly selected. A total of 550 college students fully participated in the actual evaluation and completed the general well-being scale, mobile phone addiction index scale, self-esteem scale, and social support scale. SPSS17.0 was used to analyze the data. The results show that: (1) Self-esteem partially mediates the relationship between mobile phone dependence and subjective well-being. Mobile phone dependence not only has a direct influence on subjective well-being, but also influences subjective well-being indirectly by self-esteem; (2) The mediating effect of self-esteem between mobile phone dependence and subjective well-being is moderated by social support. Social support moderates the second path of the mediation, and the higher the social support, the greater the degree of self-esteem on subjective well-being. For the management of mobile phone dependence of college students, more attention needs to be paid to the personality characteristics of different students. In addition, there should be efforts to avoid blindly educating students and instead to increase their social support and create a good atmosphere on campus and in society. Only in this way can they improve their subjective well-being.