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There are many outstanding questions about how to control the global COVID-19 pandemic. The information void has been especially stark in the World Health Organization Africa Region, which has low per capita reported cases, low testing rates, low access to therapeutic drugs, and has the longest wait for vaccines. As with all disease, the central challenge in responding to COVID-19 is that it requires integrating complex health systems that incorporate prevention, testing, front line health care, and reliable data to inform policies and their implementation within a relevant timeframe. It requires that the population can rely on the health system, and decision-makers can rely on the data. To understand the process and challenges of such an integrated response in an under-resourced rural African setting, we present the COVID-19 strategy in Ifanadiana District, where a partnership between Malagasy Ministry of Public Health (MoPH) and non-governmental organizations integrates prevention, diagnosis, surveillance, and treatment, in the context of a model health system. These efforts touch every level of the health system in the district-community, primary care centers, hospital-including the establishment of the only RT-PCR lab for SARS-CoV-2 testing outside of the capital. Starting in March of 2021, a second wave of COVID-19 occurred in Madagascar, but there remain fewer cases in Ifanadiana than for many other diseases (e.g., malaria). At the Ifanadiana District Hospital, there have been two deaths that are officially attributed to COVID-19. Here, we describe the main components and challenges of this integrated response, the broad epidemiological contours of the epidemic, and how complex data sources can be developed to address many questions of COVID-19 science. Because of data limitations, it still remains unclear how this epidemic will affect rural areas of Madagascar and other developing countries where health system utilization is relatively low and there is limited capacity to diagnose and treat COVID-19 patients. Widespread population based seroprevalence studies are being implemented in Ifanadiana to inform the COVID-19 response strategy as health systems must simultaneously manage perennial and endemic disease threats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SN declared a shared affiliation, with no collaboration, with one of the authors AG, to the handling editor at the time of the review., (Copyright © 2021 Rakotonanahary, Andriambolamanana, Razafinjato, Raza-Fanomezanjanahary, Ramanandraitsiory, Ralaivavikoa, Tsirinomen'ny Aina, Rahajatiana, Rakotonirina, Haruna, Cordier, Murray, Cowley, Jordan, Krasnow, Wright, Gillespie, Docherty, Loyd, Evans, Drake, Ngonghala, Rich, Popper, Miller, Ihantamalala, Randrianambinina, Ramiandrisoa, Rakotozafy, Rasolofomanana, Rakotozafy, Andriamahatana Vololoniaina, Andriamihaja, Garchitorena, Rakotonirina, Mayfield, Finnegan and Bonds.)