(1) Background: The aims of this study were to examine trends in the incidence, clinical characteristics, and in-hospital outcomes of patients hospitalized with pulmonary embolism in Spain and to identify factors associated with in-hospital mortality (IHM). (2) Methods: We included all patients who were hospitalized for pulmonary embolism between 2001 and 2018. Data were collected from the Spanish National Hospital Discharge Database. (3) Results: We identified 241,821 hospitalizations for pulmonary embolism during the study period. The incidence of pulmonary embolism increased from 20.49 cases per 100,000 inhabitants in the period 2001–2002 to 35.9 cases in the period 2017–2018 (p < 0.001). After controlling for possible confounders, there was a significant increase in the incidence over the study period (adjusted incidence rate ratio 1.53, 95% Confidence Interval I 1.51–1.56). The median length of hospital stay was 11 days in the period 2001–2002, decreasing to seven days in the period 2017–2018 (p < 0.001). For the total time period, the crude IHM rate was 9.51%. After multivariable adjustment, IHM decreased significantly over time. The IHM was significantly higher in women, in patients suffering from more comorbidities, and in those with a massive pulmonary embolism. (4) Conclusions: Our results revealed an increase in the incidence of pulmonary embolism hospitalizations from 2001 to 2018 in Spain, with older patients being the most affected.