Prior antibiotic use may be a factor in the rising incidence of colorectal cancer seen in those under 50 years of age (early-onset colorectal cancer [EOCRC]); however, the few studies to examine this link have reported conflicting results. Therefore, we evaluated the association between oral antibiotic use in adulthood and EOCRC in a large integrated healthcare system in the United States. A population-based nested case-control study was conducted among Kaiser Permanente Northern California patients 18-49 years of age diagnosed with EOCRC (adenocarcinoma of the colon or rectum) in 1998-2020 who had ≥2 years of continuous pharmacy benefit prior to diagnosis. Cases were matched 4:1 to healthy controls on birth year, sex, race and ethnicity, medical facility, and duration of pharmacy benefit. Antibiotic exposure >1 year before the diagnosis/index date was assessed using prescribing records. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). A sensitivity analysis was performed among those with ≥10 years of continuous prescribing records. 1359 EOCRC cases were matched to 4711 healthy controls. Antibiotic use in adulthood was not significantly associated with EOCRC in unadjusted or adjusted analyses (adjusted OR: 1.04; 95% CI: 0.94-1.26). No associations were seen for cumulative number of oral antibiotic dispensations or for any prior period of antibiotic exposure. In a large United States healthcare setting, there was no conclusive evidence of an association between oral antibiotic use in adulthood and risk of EOCRC.