Background and aim It has been demonstrated that marginalized populations across the U.S. have suffered a disproportionate burden of the coronavirus disease 2019 (COVID-19) pandemic, illustrating the role that social determinants of health play in health outcomes. To better understand how these vulnerable and high-risk populations have experienced the pandemic, we conducted a qualitative study to better understand their experiences from diagnosis through recovery. Methods We conducted a qualitative study of patients in a North Carolina healthcare system’s registry who tested positive for COVID-19 from March 2020 through February 2021, identified from population-dense outbreaks of COVID-19 (hotspots). We conducted semi-structured phone interviews in English or Spanish, based on patient preference, with trained bilingual study personnel. Each interview was evaluated using a combination of deductive and inductive content analysis to determine prevalent themes related to COVID-19 knowledge, diagnosis, disease experience, and long-term impacts. Findings The 10 patients interviewed from our COVID-19 hotspot clusters were of equal distribution by sex, predominantly Black (70%), aged 22–70 years (IQR 45–62 years), and more frequently publicly insured (50% Medicaid/Medicare, vs 30% uninsured, vs 20% private insurance). Major themes identified included prior knowledge of COVID-19 and patient perceptions of their personal risk, the testing process in numerous settings, the process of quarantining at home after a positive diagnosis, the experience of receiving medical care during their illness, and difficulties with long-term recovery. Discussion Our findings suggest areas for targeted interventions to reduce COVID-19 transmission in these high-risk communities, as well as improve the patient experience throughout the COVID-19 illness course.