Background <p>Depression is a pervasive public health problem among college students. Rumination has been increasingly recognized as a risk factor, but little is known about the mediating role underlying the relation between rumination and depression. The current study examined the mediating role of loneliness and the moderating role of gender.</p> Methods <p>The survey was conducted in May 2018. 814 Chinese college students (363 males, 451 females, mean age = 20.75, <i>SD</i> = 0.90) completed three questionnaires regarding rumination, loneliness, and depression.</p> Results <p>The results showed that rumination was significantly associated with depression. This relationship was partially mediated by loneliness. Furthermore, the direct effect was moderated by gender. The relationship between rumination and depression was stronger for male students relative to the females. </p> Conclusion <p>These findings deepen our understanding of the mediating role underlying the relationship between rumination and depression. In addition, these findings encourage to design psychological interventions to reduce the level of depression.</p>