Background: A large number of socio-demographic, economic, environmental, and psychosocial changes have contributed to the epidemiological transition of African countries and fundamentally shifted the primary drivers of health. Cohort studies are essential for understanding and improving population health, but remain scarce in sub-Saharan Africa. Objective: The main objective of the Taabo multi-generational cohort project (Taabo MGC) is to establish a large, regionally representative multi-generational cohort. The cohort will be established within the Taabo Health and Demographic Surveillance Site (HDSS) and used for studying the life-course and intergenerational dynamics of disease in south-central Côte d’Ivoire. Methods: The Taabo MGC focuses on children born between January 1, 2024, and December 31, 2025 in the Taabo HDSS, as well as their parents, grandparents and great-grandparents. Eligible women and their children are enrolled during pregnancy and those not reported during pregnancy are enrolled after the birth. After enrollment of pregnant women biological ancestors of the index child who are still alive and living in the study area are recruited into the cohort. The cohort is expected to enroll at least 3’000 pregnant women and their children, as well as the infants’ fathers, grandparents, and great-grandparents with an expected sample size of approximately 15’000 individuals. To ensure the entire local population is covered in this study, we will also include 100 adults without children in the study. The baseline assessments covers data on demographics, household wealth, tobacco and alcohol consumption, diet, physical activity, health history, quality of life, environmental exposures, depression, anxiety, stress, resilience, obstetric history, birth outcomes, cognitive function and physical performance for elders. We also collect anthropometric measurements, blood pressure, hemoglobin levels and conduct a malaria infection test with all participants. Results: We expect this to become one of the largest current cohort studies in Sub-Saharan Africa. Through the HDSS, we will be able to follow all cohort members over time to verify and monitor survival and general health status. Conclusions: The Taabo MGC is designed to become one of the largest cohort studies in the region. We hope to use this study as a platform for future observational and interventional studies at the local level and contribute to the much-needed evidence base on lifetime disease risk in south-central Côte d'Ivoire and sub-Saharan Africa.