The fundamental organization of the human brain is established before birth, with rapid growth continuing over the first postnatal years. Children exposed before or after birth to various biological (e.g., substance exposure) or psychosocial hazards (e.g., maltreatment) are at elevated likelihood of deviating from a typical developmental trajectory, which in turn can be associated with psychological, behavioral, and physical health sequelae. In the HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, brain, physical, biological, cognitive, behavioral, social, and emotional development is being examined starting in pregnancy and planned through age 10 (data are sampled at varying degrees of granularity depending on age, with more dense sampling earlier in life). HBCD aims to determine the short- and long-term impacts of a variety of both harmful and protective factors, including prenatal substance use, on developmental trajectories through early childhood. Organized as a nationwide consortium across 27 sites, the HBCD Study will collect multimodal data that will be made publicly available on a yearly basis, through a data use application and approval process. Here we provide an overview of the HBCD Study design, sampling, protocol development, and data management. Data collected through HBCD will be fundamental to informing future prenatal and early childhood interventions and policies to promote wellbeing and resilience in all children.