Cytokine storm induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a major pathological feature of Coronavirus Disease 2019 (COVID-19) and a crucial determinant in COVID-19 prognosis. Understanding the mechanism underlying the SARS-CoV-2-induced cytokine storm is critical for COVID-19 control. Here, we identify that SARS-CoV-2 ORF3a and host hypoxia-inducible factor-1 alpha (HIF-1 alpha) play key roles in the virus infection and pro-inflammatory responses. RNA sequencing shows that HIF-1 alpha signaling, immune response, and metabolism pathways are dysregulated in COVID-19 patients. Clinical analyses indicate that HIF-1 alpha production, inflammatory responses, and high mortalities occurr in elderly patients. HIF-1 alpha and pro-inflammatory cytokines are elicited in patients and infected cells. Interestingly, SARS-CoV-2 ORF3a induces mitochondrial damage and Mito-ROS production to promote HIF-1 alpha expression, which subsequently facilitates SARS-CoV-2 infection and cytokines production. Notably, HIF-1 alpha also broadly promotes the infection of other viruses. Collectively, during SARS-CoV-2 infection, ORF3a induces HIF-1 alpha, which in turn aggravates viral infection and inflammatory responses. Therefore, HIF-1 alpha plays an important role in promoting SARS-CoV-2 infection and inducing pro-inflammatory responses to COVID-19.