Background Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are challenging medical problems. Previous studies have shown that 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) plays an important role in the diagnosis of FUO, but few studies have explored this diagnostic technique in relation to IUO. Purpose To systematically review and perform a meta-analysis of published data on the diagnostic performance of PET/CT in the diagnosis of FUO and IUO. Material and Methods A comprehensive literature search was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines published in March 2018. Meta-analysis of diagnostic performance was performed using STATA 12.0 software. Subgroup analysis was performed by stratification based on study design, number of patients, geographic area, and final diagnosis based on 18F-FDG PET/CT. Meta-regression analyses were performed to recognize heterogeneity. Results Our meta-analysis included 23 studies, comprising a total sample size of 1927 patients. The pooled diagnosis performance was calculated with a per-patient-based analysis: sensitivity = 0.84 (95% confidence interval [CI] = 0.79-0.89), specificity = 0.63 (95% CI = 0.49-0.75), positive likelihood ratio = 2.3 (95% CI = 1.5-3.4), negative likelihood ratio = 0.25 (95% CI = 0.16-0.38), diagnostic odds ratio = 9 (95% CI = 4.0-20), and AUC = 0.84 (95% CI = 0.81-0.87). Conclusion In patients with non-specific symptoms and signs, 18F-FDG PET/CT is very helpful for recognizing and excluding diseases, directing further diagnostic decisions, and avoiding unnecessary invasive examinations. We recommend that 18F-FDG PET/CT should be considered among the first-line diagnostic tools for patients with FUO and IUO.