BACKGROUND: Low-cost, household-level water, sanitation, and hygiene (WASH) and nutrition interventions can reduce pediatric antibiotic use, but the mechanism through which interventions reduce antibiotic use has not been investigated. METHODS: We conducted a causal mediation analysis using data collected between September 2013 and October 2015 from a cohort nested within the WASH Benefits Bangladesh cluster-randomized trial (NCT01590095). Among a subsample of children within the WASH, nutrition, nutrition + WASH, and control arms (N = 1409 children; 267 clusters), we recorded caregiver-reported antibiotic use at ages 14 and 28 months and collected stool at age 14 months. Our primary outcome was any caregiver-reported antibiotic use by index children within the past 30 or 90 days measured at age 14 and 28 months. Mediators included caregiver-reported child diarrhea, acute respiratory infection (ARI), and fever; and enteric pathogen carriage in stool measured by qPCR. Both intervention-mediator and mediator-outcome models were controlled for mediator-outcome confounders. FINDINGS: The receipt of any WASH or nutrition intervention reduced caregiver-reported antibiotic use through all pathways in the past month by 5.5 percentage points (95% CI 1.2, 9.9), from 49.5% (95% CI 45.9%, 53.0%) in the control group to 45.0% (95% CI 42.7%, 47.2%) in the pooled intervention group. When separating this effect into different pathways, we found that interventions reduced antibiotic use by 0.6 percentage points (95% CI 0.1, 1.3) through reduced diarrhea, 0.7 percentage points (95% CI 0.1, 1.5) through reduced ARI with fever, and 1.5 percentage points (95% CI 0.4, 3.0) through reduced prevalence of enteric viruses. Interventions reduced antibiotic use through any of these measured mediators by 2.1 percentage points (95% CI -0.3, 4.5). INTERPRETATION: WASH and nutrition interventions reduced pediatric antibiotic use through the prevention of enteric and respiratory infections in a rural, low-income population. Given that many of these infections are caused by viruses or parasites, WASH and nutrition interventions may help reduce inappropriate antibiotic use in similar settings. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases.