Conventional methods may fail to identify the cause of pleural effusion (PE), thus establishing reliable biomarkers is deemed necessary. This study aimed at examining the role of vascular endothelial growth factor (VEGF) as a biomarker in the differentiation between malignant and benign PEs in adults. A comprehensive literature search in PubMed (Medline), Scopus (ELSEVIER), and Cochrane Central Register of Controlled Trials (CENTRAL) databases was conducted using keywords. We included studies that evaluated pleural and/or serum levels of VEGF among patients presenting with undiagnosed PE and the association between these levels and the final diagnosis. We performed a meta‐analysis to calculate the summary effect using the random effects model. Statistical analysis was performed with the statistical package for meta‐analysis Comprehensive Meta‐Analysis. Twenty studies were included in the systematic review, while 11 of them in the meta‐analysis. Pleural fluid VEGF levels among patients with malignant PE were increased by 1.93 ng/mL as compared to patients with benign PE (95% CI: 1.32–2.54, Q = 173, df (Q): 10, I
2 = 94.2%, P < 0.05). Serum VEGF levels among patients with malignant PE were increased respectively by 1.90 ng/mL (95% CI: 0.93–2.88, Q = 182, df (Q): 6, I
2 = 96.7%, P < 0.05). This study showed that malignant PEs were associated with higher levels of both pleural fluid and serum VEGF. VEGF appears to represent a promising biomarker for the differential diagnosis between benign and malignant PEs.