The objective of the Reducing Enteropathy, Undernutrition, and Contamination in the Environment (REDUCE) program is to identify exposure pathways to fecal pathogens that are significant contributors to morbidity among young children in the Democratic Republic of the Congo (DRC), and on developing and evaluating scalable interventions to reduce fecal contamination from these pathways. This prospective cohort study of 270 children under 5 years of age was conducted in rural South Kivu, DRC, to investigate the association between Escherichia coli in hand rinse, soil, food, object, surface, stored water, and water source samples and child developmental outcomes. Child developmental outcomes were assessed by communication, fine motor, gross motor, personal social, problem-solving, and combined scores measured by the Extended Ages and Stages Questionnaire (EASQ) at a 6-month follow-up. Children having E. coli present in the soil in their play spaces had significantly lower combined EASQ z scores (coefficient: −0.38 (95% CI: −0.73, −0.03)). E. coli on children’s hands was associated with lower communication EASQ z scores (−0.37 (95% CI: −0.0.10, −0.01), and E. coli in stored drinking water was associated with lower gross motor EASQ z scores (−0.40 (95% CI: −0.68, −0.12). In the REDUCE cohort study, E. coli in child play spaces, on children’s hands, and in stored drinking water was associated with lower developmental outcome scores (communication, gross motor, fine motor, and problem-solving skills). These results suggest the need for interventions to reduce fecal contamination in the household environment to protect the cognitive development of susceptible pediatric populations in rural DRC.