Background: The world has high hopes of vaccination against COVID-19 to protect the population, boost economies and return to normal life. Vaccination programmes are being rolled out in high income countries, but the pandemic continues to progress in many low-and middle-income countries (LMICs) despite implementation of strict hygiene measures. We aim to present a comprehensive research protocol that will generate epidemiological, sociological and anthropological data about the COVID-19 epidemic in Burkina Faso, a landlocked country in West Africa with scarce resources. Methods: We will perform a multidisciplinary research using mixed methods in the two main cities in Burkina Faso (Ouagadougou and Bobo-Dioulasso). Data will be collected in the general population and in COVID-19 patients, caregivers and health care professionals in reference care centers: (i) to determine cumulative incidence of SARS-CoV-2 infection in the Burkinabe population using blood samples collected from randomly selected households according to the WHO-recommended protocol; (ii) develop a score to predict severe complications of COVID-19 in persons infected with SARS-CoV-2 using retrospective and prospective data; (iii) perform semi-structured interviews and direct observation on site, to describe and analyze the healthcare pathways and experiences of patients with COVID-19 attending reference care centers, and to identify the perceptions, acceptability and application of preventive strategies among the population. Discussion: This study will generate comprehensive data that will contribute to improving COVID-19 response strategies in Burkina Faso. The lessons learned from the management of this epidemic may serve as examples to the country authorities to better design preventive strategies in the case of future epidemics or pandemics. The protocol was approved by the Ministry for Health (N° 2020-00952/MS/CAB/INSP/CM) and the Health Research Ethics Committee in Burkina Faso (N° 2020-8-140).