BackgroundDoctor-diagnosed plant allergy (DPA) in children has emerged as a significant global public health concern. However, the role of antibiotics and indoor environmental factors (IEFs) in childhood DPA remains unknown. ObjectiveTo investigate the correlations between childhood DPA and exposure to antibiotics and IEFs during different time periods. MethodsA retrospective cohort study of 8,689 preschoolers was performed in Changsha, China. We collected data on each child's health outcomes, antibiotics use and home environment by a questionnaire, as well as temperature and air pollutants in Changsha, and calculated personal exposure to temperature and pollutants. Multiple logistic regression models were used to assess the independent and joint effects of antibiotics and IEFs on childhood DPA. ResultsLife-time and early-life antibiotics use was associated with childhood DPA with ORs (95% CI) = 1.58 (1.15–2.17) and 1.33 (1.04–1.69), with a higher risk for early-life exposure than later-life exposure. Renovation-specific indoor air pollution (IAP) during pre-birth (1 year before pregnancy and pregnancy) and smoke-specific IAP during early life (pregnancy and first year) had significantly impacts on childhood DPA. Furthermore, dampness-specific allergens throughout lifetime elevated the risk of DPA, with ORs ranging from 1.34 (1.00–1.81) to 1.93 (1.44–2.59). Moreover, life-time and early-life antibiotic use significantly increased the DPA risk attributed to some specific IEFs, such as ETS especially grandparental smoking, exposure during first year and previous year, with a significant interaction. ConclusionsLife-time and early-life exposure to antibiotics and IEFs independently and jointly played key roles in the development of DPA, supporting the “fetal origin of childhood PA” hypothesis.