Background Nationwide hospital admissions data series have contributed to a reliable assessment of the changing epidemiology of infective endocarditis, even though conclusions are not uniform. We sought to use a recent populational series to describe the temporal trends on the incidence of infective endocarditis, its clinical characteristics and outcome results, in Portugal. Methods A nationwide retrospective temporal trend study on the incidence and clinical characterization of patients hospitalized with infective endocarditis, between 2010 and 2018. Results 7574 patients were hospitalized with infective endocarditis from 2010 to 2018 in Portuguese public hospitals. The average length of hospitalization was 29.3 ± 28.7 days, predominantly men (56.9%), and 47.1% had between 60 and 79 years old. The most frequent infectious agents involved were Staphylococcus (16.4%) and Streptococcus (13.6%). During hospitalization, 12.4% of patients underwent heart valve surgery and 20% of the total cohort died. After a 1-year post-discharge follow-up, 13.2% of the total initial cohort had had heart valve surgery and 21.2% in total died. The annual incidence of infective endocarditis was 8.31 per 100,000 habitants, being higher in men (9.96 per 100,000 in males versus 6.82 in females, p < 0.001) and increased with age, peaking at patients 80 years old or older (40.62 per 100,000). In-hospital mortality rate significantly increased during the analyzed period, the strongest independent predictors being ischemic or hemorrhagic stroke, sepsis, and acute renal failure. Younger age and cardiac surgery had a protective effect towards a fatal outcome. Conclusions In Portugal, between 2010 and 2018, the incidence of infective endocarditis presented a general growth trend with a deceleration in the most recent years. Also, a significant rate of in-hospital complications, a mildly lower than expected stable surgical rate and a still high and growing mortality rate were noted.