Background Previous research has revealed sex‐related differences in outcomes for people admitted to hospitals for ischemic stroke. We aimed to analyse the incidence, use of invasive procedures and in‐hospital outcomes of ischemic stroke in Spain (2016‐2018) using the Spanish National Hospital Discharge Database. We sought sex‐related differences in incidence and in‐hospital outcomes over time. Methods We estimated the incidence of ischemic stroke in men and women. We analysed comorbidities (Charlson's comorbidity index, cardiovascular risk factors, alcohol abuse and atrial fibrillation), procedures (mechanical ventilation, endovascular thrombectomy and thrombolytic therapy) and outcomes. We matched each woman with a man with identical age, type of ischemic stroke and year of hospitalisation. We built Poisson regression models to obtain adjusted incidence rate ratios (IRRs). We tested in‐hospital mortality (IHM) with logistic regression analyses. Results Ischemic stroke was coded in 172 255 patients aged ≥35 years (92 524 men 53.7%). Men showed higher incidence rates (216.9 vs. 172.3/105; P < .001; IRR = 1.57 (95% CI:1.55‐1.59) than women. After matching, the use of endovascular thrombectomy (5.1% vs. 4.0%; P < .001) and thrombolytic therapy (7.6% vs. 6.8%; P < .001) was higher among women. IHM was significantly higher in women than in matched men (11.2% vs. 10.4%; P < .001). Women had a lower IHM than matched men when endovascular thrombectomy (9.4% vs. 12.1%; P = .001) or thrombolytic therapy (6.7% vs. 8.3%; P = .003) was coded. Patients of both sexes admitted for ischemic stroke who received thrombolytic therapy had lower IHM (OR = 0.76; 95% CI:0.68‐0.85 among men; and OR = 0.58; 95% CI:0.52‐0.64 among women), but endovascular thrombectomy was associated with a lower IHM only among women (OR = 0.58; 95% CI:0.51‐0.66). After multivariable adjusting, women admitted to the hospital for ischemic stroke had a significantly higher IHM than men (OR = 1.16; 95% CI:1.12‐1.21). Conclusion Men had higher incidence rates of ischemic stroke than women. Women more often underwent thrombolytic therapy and endovascular thrombectomy but had a higher IHM.