Abstract Background Understanding the epidemiology of infective endocarditis (IE) is crucial in the context of an aging population, increased comorbidities, and the heightened occurrence of healthcare-associated cases. Comprehensive data on causative agents, affected valves, and associated mortality are essential for current clinical practice. Methods This systematic review was conducted according to the PRISMA guidelines. A random effects model meta-analysis was conducted. Eligible studies reporting outcomes on IE were identified through a search of the PubMed/Medline database from 2010 to 2021. Results One hundred-thirty-three studies with 132,584 patients from six continents were included in the analysis. The most common causative agents of IE were Staphylococci species in 36% of cases, followed by Streptococci species in 26% of cases and Enterococci species in 10% of cases. Of the studies providing further speciation, the predominant species was Staphylococcus aureus with an incidence of 29%, followed by Viridans Streptococcus with an incidence of 12%. We found an in-hospital/30-day mortality of 17% (CI: 16%-19%) from 109 studies worldwide. In the subgroup analysis, the highest mortality rates were observed in Latin America 33% (CI: 28%-38%) and Africa 25% (CI: 21%-30%), while the lowest mortality rates were reported in Oceania 13% (CI: 8%-19%), followed by North America 14% (CI: 11%-18%), Asia 15% (CI: 12%-18%), and Europe 17% (CI: 16%-19%). The aortic valve was affected in 46% of cases, followed by the mitral valve in 43%. Tricuspid valve IE and multivalvular IE were identified in 7% and 14% of the cases, respectively. Conclusion Our study highlights the shift in epidemiological profile of IE over the last decade with S. aureus identified as the most common causative microorganism of IE in almost one third of cases. IE remains a highly morbid and fatal condition with high mortality rates even in tertiary and high-expertise centers worldwide. While left-sided IE is by far more common, right-sided IE and multivalvular IE are not rare entities and should be considered early in the differential of patients presenting with suspected IE to decrease the risk of future complications.Global burden of infective endocarditis.