Background: Endoscopic ultrasound-guided RFA (EUS-RFA) is a minimally invasive emerging modality that may be an alternative to surgical resection for the management of unresectable pancreatic cancer (UPC). In this review, we highlighted the efficacy, clinical and technical success of the EUS-RFA for UPC. Methods: Studies were selected with a comprehensive search strategy for EUS-RFA and pancreatic cancer on PubMed, Google Scholar, and Embase databases as of October 2021. The primary outcomes were the technical (TS) and clinical success rate (CS) of the EUS-RFA procedure, while the secondary outcome was the adverse events (AEs) rate. Results: Twelve studies including 114 patients with 50% (57) females were included. Common pancreatic tumors were locally advanced pancreatic ductal adenocarcinoma (LAPDAC) 38.3% (49), followed by nonfunctional neuroendocrine tumor (NNET) 32% (41), pancreatic cystic neoplastic lesions 14.8% (19), insulinoma 12.5% (16) and others 2.3% (3). The most common site of the tumor was pancreatic head 45.7% (59) followed by body, neck, and tail 47.6% (61). The average number of ablation sessions per patient was 1.4 based on the total of 115 EUS-RFA sessions performed in 84 neoplastic lesions. The pooled TS rate of EUS-RFA calculated from the total number of procedures was 99.2% [95% CI = 0.90-0.98, I² = 0%]. The pooled CS rate calculated from the total number of pancreatic lesions was 91.9% [95% CI = 0.77-0.92, I² = 0%]. Clinical improvement in symptoms was reported in five studies whereas complete resolution or decrease in tumor size was reported in all studies. The pooled AEs rate was 24.6% [95% CI = 0.17-0.39, I² = 30%]. Common AEs were abdominal pain 10.5% (12), and pancreatitis 3.5% (4). Conclusions: EUS-RFA is a promising and safe modality that can be used for the management of UPC in selected patients with a high TS (99.2%) and CS rates (91.9%). Large clinical trials are needed to identify safety, clinical outcomes, and overall survival benefits of EUS-RFA.