Acid blocker therapy (ABT) has become common in cystic fibrosis (CF), despite insufficient evidence for benefits and studies showing potentially negative effects. We examined associations between ABT usage and growth, gut microbiome (GM), and early-onset lung disease in young children with CF. One hundred forty-five infants with CF born during 2012-2017, diagnosed through newborn screening by age 3 months and followed to 36 months of age at six CF centers were evaluated. Longitudinal data on growth, pancreatic functional status, pulmonary symptoms, and acid blocker medications were prospectively collected. Early-onset lung disease severity was evaluated by a clinical scoring system. GM composition was assessed by 16S rRNA methodology. ABT use before age 3 years was frequent, with 81 (56%) of patients on H2 receptor antagonist (H2RA) or proton pump inhibitor (PPI), and higher among pancreatic insufficient (60%) versus pancreatic sufficient (26%) children. H2RA was commonly prescribed in infancy before transitioning to PPI. Growth improvements were not significantly greater, while GM α-diversity at 3 years of age was significantly lower and early-onset lung disease more severe, in persistent ABT users compared to nonusers of ABT. In our cohort of young children with CF, early and persistent ABT use was not associated with significant growth benefits and instead showed associations with reduced GM diversity and negative effects on early-onset lung disease. Consequentially, there is a critical need for systematic evaluation and comprehensive risk-benefit analysis of ABT to ensure proper guidelines for children with CF.