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Background: Infant antibiotic exposure may be associated with childhood asthma development. Objective: To examine and detail this association considering potential confounders. Study design: PubMed, EMBASE, Web of Science, and the Cochrane Library were searched for publications from January 2011 to March 2021. Eligible studies were independently reviewed to extract data and assess quality. Random effect model was used to pool odds ratio (OR) and corresponding 95% confidence intervals (CIs). Results: A total of 52 studies were included. The association of infant antibiotic exposure and childhood asthma was statistically significant for overall analysis (OR, 1.37; 95% CI, 1.29–1.45) and for studies that addressed reverse causation (RC) and confounding by indication (CbI) (1.19; 95% CI, 1.11–1.28). Significance remained after stratification by adjustment for maternal antibiotic exposure, medical consultation, sex, smoke exposure, parental allergy, birth weight, and delivery mode. In detailed analyses, macrolides (OR, 1.56; 95% CI, 1.31–1.86), antibiotic course≥5 (OR, 1.79; 95% CI, 1.36–2.36), exposure within 1 week of birth (OR, 1.82; 95% CI, 1.34–2.47), asthma developed among 1–3 years (OR, 1.84; 95% CI, 1.63–2.08), short time lag between exposure and asthma onset (OR, 2.05; 95% CI, 1.91–2.20), persistent asthma (OR, 2.61; 95% CI, 1.49–4.59), and atopic asthma (OR, 2.14; 95% CI, 1.58–2.90) showed higher pooled estimates. Conclusion: Infant antibiotic exposure is associated with increased risk of childhood asthma considering confounding, and the association varied with different settings of exposure and outcomes. This highlights the need for prevention of asthma after early antibiotic exposure. Heterogeneity among studies called for caution when interpretation.