Introduction: Postoperative pancreatic fistula (POPF) remains one of the most challenging complications following pancreatoduodenectomy, contributing significantly to morbidity and mortality. This study explores the relationship between clinical, biochemical, and surgical factors and the development of POPF, with a focus on identifying predictors. Methods: This observational study was conducted in Dhaka Medical College & Hospital (DMCH), Dhaka, from January 2023 to December 2023. 30 patients with the Whipples procedure were selected as study subjects by purposive simple random sampling technique. Analysis was done manually by MS Word & MS Excel worksheet and SPSS. The unpaired t-test and Chi-square test were done for data analysis. Result: POPF was significantly associated with a smaller main pancreatic duct diameter (≤3 mm, p = 0.006) and soft pancreatic texture (p = 0.00005). Elevated drain fluid amylase levels, particularly on postoperative day 5, highlighted its role in the early detection of POPF. Periampullary carcinoma was the most common diagnosis overall, though only chronic pancreatitis showed a significant association with POPF (p = 0.032). The duct-to-mucosa anastomotic technique significantly reduced the risk of POPF compared to the dunking method (p = 0.00001). Other variables, including blood loss and procedure type, were not significantly linked to POPF development. Conclusion: This study highlights that postoperative pancreatic fistula (POPF) following pancreatoduodenectomy is strongly influenced by factors such as small main pancreatic duct diameter (≤3 mm), soft pancreatic texture, and the anastomotic technique used. Elevated drain fluid amylase levels in the early postoperative period emerged as a reliable marker for POPF risk.