Overactive Bladder (OAB), characterized by urinary urgency with frequency and nocturia, affects approximately 12 % of the adult female population's quality of life. Estrogen, known for its role in modulating lower urinary tract function, is commonly prescribed to alleviate urogenital symptoms in menopausal women. However, the efficacy of oral estrogen in treating OAB remains controversial. This study explores the association between oral estrogen and OAB using data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. Participants were categorized based on their estrogen exposure and OAB status, with a logistic regression analysis employed to evaluate the relationship between oral estrogen and OAB, controlling for variables such as age, race, education, income, and health conditions. Additionally, network pharmacology and molecular docking were conducted to investigate the potential mechanisms underlying estrogen's effects on OAB. Our findings indicate that oral estrogen is an independent risk factor for OAB, particularly in women under 60. Moreover, the study highlights albumin and inflammation's central role in the estrogen-OAB interaction. These results suggest the need for cautious consideration of oral estrogen therapy in managing OAB and underscore the importance of personalized treatment approaches based on individual risk profiles.