Introduction Existing evidence remains conflicting regarding the association between oral hormonal contraceptive (OCP) use and the risk of acute ischemic stroke (AIS). Large‐scale analyses and observational data evaluating this clinical question in recent years are scarce, despite widespread use of hormonal contraception in adult females of child‐bearing age. Modern OCP formulations contain lower doses of estrogen, the putative causative agent for AIS in this population, and underscores the need to re‐evaluate the risk initially demonstrated in older formulations containing higher levels of estrogen. Methods Hospitalizations for female patients aged 15‐50 were identified in the National Inpatient Sample (NIS) registry from 2015‐2020, excluding admissions associated with pregnancy or the postpartum period. The study exposure was use of OCPs and the primary endpoint was AIS, identified by International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM) coding. Propensity score (PS) adjustment by inverse probability weighting (IPW) was used to mimic the effects of randomization by balancing baseline clinical characteristics associated with stroke between OCP and non‐OCP users to reduce measured confounding. In addition to age and race/ethnicity, a battery of more than forty confounding covariates representing established risk factors for AIS in the general and young population were identified (cardiovascular disease, lifestyle risk factors, congenital abnormalities, vasculopathies, hypercoagulable states, migraine with aura, among others) and balanced between OCP and non‐OCP users. Sensitivity testing was performed by evaluating stroke incidence in a sub‐group of patients without any risk factors present and by assessing a negative control (head trauma), with which an association of OCP use would not be expected. The effect size of the association between OCPs and AIS was presented as an adjusted odds ratio (aOR) with 95% confidence interval (CI), with statistical significance evaluated at p < 0.001. Results PS adjustment by IPW to balance all available AIS risk factors between OCP users and non‐users yielded 23,253,209 hospitalizations, 11,654,398 (50.1%) of which were associated with OCP use. The incidence of AIS was significantly greater in OCP users compared to non‐OCP users (2.8% vs. 0.4%; aOR 7.50, 95% CI 7.43 to 7.58; p < 0.001). Sub‐group analysis of hospitalizations without any stroke risk factors also demonstrated a significant association of OCP use with the development of AIS (1.3% vs. 0.1%; aOR 14.84, 95% CI 13.16 to 16.72; p < 0.001) following adjustment for age and race/ethnicity. In negative control analysis, OCP use was not associated with admissions associated with head trauma (1.4% vs. 1.4%; OR 1.03, 95% CI 0.95 to 1.10; p = 0.485). Conclusion Retrospective observational data from the United States in recent years suggests an association between OCP use and AIS, independent of well‐established risk factors for stroke and despite widespread adoption of lower estrogen formulations.