Background: Infectious endocarditis is a life-threatening disease, requiring prompt and accurate diagnosis. The aim of this article is to perform a systematic review and meta-analysis of the literature to estimate the performance of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for the diagnosis of native valve endocarditis (NVE). Methods: Selected articles evaluating the diagnostic accuracy of 18F-FDG PET/CT in patients with suspected NVE, resulting from a comprehensive literature search through the PubMed/MEDLINE and Cochrane library databases until April 2020, were included for the systematic review and meta-analysis. Results: Seven studies (351 episodes of suspected NVE) were included. 18F-FDG PET/CT yielded a pooled sensitivity of 36.3% and a pooled specificity of 99.1% for the diagnosis of NVE. The pooled positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 8.3, 0.6, and 15.3, respectively. The sensitivity increased using contemporary PET/CT device with state-of-the-art patient preparation as well as innovative image acquisitions or adding the results of 18F-FDG PET/CT in a multimodality strategy. Conclusions: In our systematic review and meta-analysis, 18F-FDG PET/CT yielded a poor pooled sensitivity with an otherwise excellent pooled specificity for the diagnosis of NVE; however, several factors may increase the sensitivity without affecting the specificity and these factors should be better evaluated in future studies.