(1) Background: A description of the trends and outcomes during hospitalization for infective endocarditis (IE) according to sex. (2) Methods: Using Spanish national hospital discharge data (2016–2020), we built Poisson regression models to compare the age-adjusted time trends for the incidence rate. We used propensity score matching (PSM) to compare the clinical characteristics and the in-hospital mortality (IHM) between men and women hospitalized with IE. (3) Results: We identified 10,459 hospitalizations for IE (33.26% women). The incidence of IE remained stable during this five-year period. The age-adjusted incidence of IE was two-fold higher among men vs. women (IRR = 2.08; 95%CI 2.0–2.17). Before PSM, women with IE were significantly older than men (70.25 vs. 66.24 years; p < 0.001) and had lower comorbidity according to the Charlson comorbidity index (mean 1.38 vs. 1.43; p = 0.019). After PSM, the IHM among women admitted for IE remained >3 points higher than that among men (19.52% vs. 15.98%; p < 0.001). (4) Conclusions: The incidence of IE was two-fold higher among men than among women. IHM was significantly higher among women after accounting for the potential confounders.