Background and AimsFor patients with high‐risk non‐ST elevation myocardial infarction (NSTEMI), current guidelines recommend an early invasive strategy within 24 h. New‐onset acute ischemic stroke (NAIS) is a rare but fatal complication of percutaneous coronary intervention (PCI). However, the effect of the timing of PCI and the risk of NAIS in NSTEMI is poorly defined.MethodsPatients with NSTEMI who underwent PCI were queried from the National Inpatient Sample Database (2016–2019) and stratified into three groups: early (<24 h), medium (24–72 h), and late (>72 h) PCI. Multivariate logistic regression models were used to determine the association between timing of PCI and NAIS.ResultsAmong 633,115 weighted hospitalizations, patients in the late PCI group had a higher incidence of NAIS (1.3%) than those in the early (0.67%) and medium (0.71%) PCI groups. Patients undergoing late PCI were older, more likely to be female, and had a greater incidence of comorbidities (e.g., diabetes mellitus, chronic pulmonary and renal illness, and atrial fibrillation) than those undergoing early or medium PCI. After adjustment, only late PCI was significantly associated with a 54% increased NAIS risk (adjusted odds ratio: 1.54 [95% confidence interval: 1.29–1.84]). Additionally, there was heterogeneity in the magnitude of risk by age and sex. Younger people (<65 years) (p for interaction <0.001) and men (interaction‐value p = 0.040) were more likely to encounter NAIS.ConclusionLate PCI was associated with a higher risk of NAIS than early PCI, particularly among men and those aged <65 years.