Background Pancreatic cancer is among the leading causes of cancer-related deaths worldwide. Resectable pancreatic cancer is typically treated with curative resection, often followed by adjuvant therapy. Despite this, recurrence rates remain high after resection. Additionally, micro-metastases may develop during the immediate postoperative period. To address this issue, neoadjuvant therapy has been proposed. This review aimed to assess the effectiveness of neoadjuvant treatment compared to surgery as first approach in resectable pancreatic cancer. Methods A comprehensive literature search was conducted up to October 2, 2024, in CENTRAL, PubMed, ProQuest, SAGE and JSTOR. Randomized controlled trials (RCTs) evaluating the effects of neoadjuvant treatment in patients with resectable pancreatic cancer were included. Results A total of 5422 articles were identified after duplicate removal. Following the screening process, 8 RCTs were included. No significant difference was observed in the overall survival (OS) among those who received neoadjuvant therapy and those who underwent upfront surgery (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.72-1.18; P=0.51). Additionally, the groups’ disease-free survival (DFS) was comparable (HR 0.98, 95%CI 0.80-1.20; P=0.83). Patients who received neoadjuvant treatment had noticeably higher R0 resection rates compared to the upfront surgery group (risk ratio 1.31, 95%CI 1.11-1.55; P=0.002). Conclusions When compared to upfront surgery, neoadjuvant therapy significantly improved the R0 resection rates, but had no significant effect on OS or DFS. More research is required to confirm the potential benefits of neoadjuvant therapy in treating resectable pancreatic cancer. © 2025 Hellenic Society of Gastroenterology.