Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating global pandemic, which has seriously affected human health worldwide. The discovery of therapeutic agents is extremely urgent, and the viral structural proteins are particularly important as potential drug targets. SARS-CoV-2 envelope (E) protein is one of the main structural proteins of the virus, which is involved in multiple processes of the virus life cycle and is directly related to pathogenesis process. In this review, we present the amino acid sequence of the E protein and compare it with other two human coronaviruses. We then explored the role of E protein in the viral life cycle and discussed the pathogenic mechanisms that E protein may be involved in. Next, we summarize the potential drugs against E protein discovered in the current studies. Finally, we described the possible effects of E protein mutation on virus and host. This established a knowledge system of E protein to date, aiming to provide theoretical insights for mitigating the current COVID-19 pandemic and potential future coronavirus outbreaks.