Background: 18F-Fluciclovine ([18F]FACBC) has been recently proposed as a synthetic radiolabeled amino acid for positron emission tomography (PET) imaging in patients with brain neoplasms. Our aim is to evaluate the diagnostic performance of [18F]FACBC PET in high-grade glioma (HGG) patients, taking into account the literature data. Methods: A comprehensive literature search was performed. We included original articles evaluating [18F]FACBC PET in the detection of HGG before therapy and for the suspicion of tumor recurrence. Pooled sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR−), and diagnostic odds ratios (DOR), including 95% confidence intervals (95% CI), were measured. Statistical heterogeneity and publication bias were also assessed. Results: ten studies were included in the review and eight in the meta-analysis (113 patients). Regarding the identification of HGG, the sensitivity of [18F]FACBC PET ranged between 85.7% and 100%, with a pooled estimate of 92.9% (95% CI: 84.4–96.9%), while the specificity ranged from 50% to 100%, with a pooled estimate of 70.7% (95% CI: 47.5–86.5%). The pooled LR+, LR−, and DOR of [18F]FACBC PET were 2.5, 0.14, and 37, respectively. No significant statistical heterogeneity or publication bias were found. Conclusions: evidence-based data demonstrate the good diagnostic accuracy of [18F]FACBC PET for HGG detection. Due to the still limited data, further studies are warranted to confirm the promising role of [18F]FACBC PET in this context.