The recent emergence of Severe Acute Respiratory Syndrome-Corona Virus 2 (SARS-CoV-2) in late 2019 and its spread worldwide caused an acute pandemic of Coronavirus disease 19 (COVID-19). COVID-19 pathologies are currently under intense scrutiny as its outbreak led to immense and urgent changes worldwide. Although many theories have been introduced on how SARS-CoV-2 enters the host, the ACE-2 receptor is shown to be the primary mechanism of SARS-CoV-2 entry. However, the mechanism behind the establishment and pathology of infection is poorly understood. As recent studies show that host mitochondria play an essential role in virus-mediated innate immune response, in this review, we will discuss, in detail, the entry and progression of SARS-CoV-2 and how mitochondria play a role in the establishment of viral infection and the development of an immune response, whether it is beneficial or not. We will also review the possible treatments that could be used to prevent the surgency of COVID-19 infection with respect to the role of mitochondria. Understanding the mitochondria-mediated SARS-CoV-2 establishment may provide a unique mechanism and conceptual advancement in finding a novel treatment for COVID-19.