Outbreaks of an epidemic, such as coronavirus disease 2019 (COVID-19), always brings about far-ranging discrimination and stigmatization to the epicenter. This was a cross-sectional survey conducted to assess experienced discrimination, internalized stigma, shame, and mental health (anxiety, depression, distress, insomnia) among college students who merely had a perceived linkage with COVID-19, and explore the linkage between discrimination and negative mental health outcomes through the mediating effects of shame and internalized stigma. A total of 995 participants (53% female) were involved in this study, in which 40.9% of college students were reported to be discriminated against because of their experience in Wuhan. The experience of COVID-19-related discrimination is indirectly associated with anxiety, depression, and insomnia, in which shame and internalized stigma play a complete mediating effect. Meanwhile, it is both directly and indirectly associated with distress through shame and internalized stigma. The findings of this study suggest that COVID-19-related discrimination is associated with shame and internalized stigma, which in turn predict psychological symptoms over time.