SummaryAn outbreak of the novel coronavirus SARS-CoV-2, the causative agent of Coronavirus Disease-2019 (COVID-19), a respiratory disease, has infected over 34,000,000 people since the end of 2019, killed over 1,000,000, and caused worldwide social and economic disruption. Due to the mechanisms of SARS-CoV-2 infection to host cells and its pathogenesis remain largely unclear, there are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Besides severe respiratory and systematic symptoms, several comorbidities may also increase risk of fatal disease outcome. Therefore, it is required to investigate the impacts of COVID-19 on pre-existing diseases of patients, such as cancer and other infectious diseases. In the current study, we have reported that SARS-CoV-2 encoded proteins and some anti-COVID-19 drugs currently used are able to induce lytic reactivation of Kaposi’s sarcoma-associated herpesvirus (KSHV), one of major human oncogenic viruses through manipulation of intracellular signaling pathways. Our data indicate that those KSHV+ patients especially in endemic areas exposure to COVID-19 or undergoing the treatment may have increased risks to develop virus-associated cancers, even after they have fully recovered from COVID-19.