Internet has become a popular medium and means to interconnect with others, especially among undergraduate students. Internet has brought great convenience to interpersonal interaction, but it also brought us problems such as with increased opportunities for inclusion, being ignored and excluded by others, a phenomenon referred to as cyber-ostracism. Studies have revealed that cyber-ostracism was an important risk factor for symptoms of depression, however, less is known about the underlying processes that may mediate or moderate this relationship. In addition, according to the Needs-threat Model of ostracism, cyber-ostracism is also distressing because it affects individuals four fundamental needs: belonging, self-esteem, control and meaningful existence. And sociometer theory also claims that poor interpersonal relationship such as perceived exclusion has negative effect on self-esteem and low self-esteem may cause the onset and maintenance of depression. Furthermore, the organism-environment interaction model and the diathesis-stress model of depression also propose that not all individuals are equally influenced by the same environment, and it is the dynamics of individual and context interactions that contribute to individuals' psychological and social adaptation. Therefore, it is important to explore the personality traits which can weaken the negative effect of cyber-ostracism. So, the present study aimed to investigate the association between cyber-ostracism and depression, as well as the mediating effect of self-esteem and moderating effect of mindfulness between them. A survey research method was conducted in which the Inventory of Cyber-ostracism Scale, Mindfulness Attention Awareness Scale, the Self-Esteem Scale as well as the Center for Epidemiological Studies Depression Scale (CES-D) were administered to 644 undergraduates (mean age = 20.08 years, SD = 1.37). Data was collected and analyzed with SPSS 20.0, and the bias-corrected percentile Bootstrap method was used to analyze the mediating effect of self-esteem and the moderating effect of mindfulness. The results indicated that: (1) After controlling for gender and age, cyber-ostracism was positively correlated with depression, while negatively correlated with self-esteem and mindfulness; mindfulness was positively correlated with self-esteem, while both mindfulness and self-esteem were negatively correlated with depression. Cyber-ostracism not only had direct positive effect on depression, but also could significantly negatively predict self-esteem; and self-esteem could significantly negatively predict depression. Self-esteem partially mediated the relationship between cyber-ostracism and depression. (2) Besides, both the direct effect of cyber-ostracism on depression and the mediating effect of self-esteem were moderated by mindfulness, and both of the two effects were stronger for the group with lower level of mindfulness. Cyber-ostracism was a negative interpersonal experience in real life, while mindfulness could alleviate it’s detrimental effect. In summary, the present study constructed a moderated mediation model of self-esteem and mindfulness to reveal the mechanism underlying the relationship between cyber-ostracism and depression, which can contribute to a better understanding of how and when Cyber-ostracism increases the risk of depression. Furthermore, it suggests that early intervention concerning diminishing negative effects of cyber-ostracism may start with increasing individual self-esteem and mindfulness.