SARS-CoV-2 infection leading to Coronavirus Disease 2019 (COVID-19) has caused more than 762 million infections worldwide, with 10–30% of patients suffering from post-acute sequelae of SARS-CoV-2 infections (PASC). Initially thought to primarily affect the respiratory system, it is now known that SARS-CoV-2 infection and PASC can cause dysfunction in multiple organs, both during the acute and chronic stages of infection. There are also multiple risk factors that may predispose patients to worse outcomes from acute SARS-CoV-2 infection and contribute to PASC, including genetics, sex differences, age, reactivation of chronic viruses such as Epstein Barr Virus (EBV), gut microbiome dysbiosis, and behavioral and lifestyle factors, including patients’ diet, alcohol use, smoking, exercise, and sleep patterns. In addition, there are important social determinants of health, such as race and ethnicity, barriers to health equity, differential cultural perspectives and biases that influence patients’ access to health services and disease outcomes from acute COVID-19 and PASC. Here, we review risk factors in acute SARS-CoV-2 infection and PASC and highlight social determinants of health and their impact on patients affected with acute and chronic sequelae of COVID-19.