Background and Objectives: Pancreatic cystic lesions (PCLs) are frequent incidental findings on cross-sectional imaging and represent a diagnostic challenge as different kinds of PCLs harbor a dissimilar risk of malignancy. Two diagnostic tools have recently been developed and introduced: through-the-needle biopsy (TTNB) and needle-based confocal laser endomicroscopy (nCLE). The aim of this meta-analysis was to compare the diagnostic yield and performance, as well as the safety profile of the two methods. Methods: This meta-analysis was performed in accordance with the PRISMA statement. Medline, Embase, Web of Science, and Cochrane Library databases were searched for studies with five or more patients undergoing either endoscopic ultrasound (EUS)-TTNB or EUS-nCLE for a PCL. Reviews, case reports, editorials, conference abstracts, and studies on exclusively solid pancreatic lesions were excluded. Outcomes of interest were diagnostic yield and performance, safety, and technical success. Results: Twenty studies with 1023 patients were included in the meta-analysis. Pooled diagnostic yield of EUS-nCLE was higher compared to EUS-TTNB (85% vs. 74%, P < 0.0001), while diagnostic performance was high and comparable for both methods (pooled sensitivity: 80% vs. 86% and pooled specificity: 80% vs. 83% for TTNB and nCLE, respectively, P > 0.05). Pooled estimate of total adverse event (AE) rate was 5% in the TTNB group and 3% in the nCLE group, P = 0.302. Technical success rates were high and comparable (94% and 99% for EUS-TTNB and nCLE, respectively; P = 0.07). Conclusion: EUS-TTNB and EUS-nCLE have a similar safety profile with a relatively low number of AEs. Technical success, sensitivity, and specificity are comparable; however, EUS-nCLE seems to have a slightly higher diagnostic yield.