Background <p>This study aimed to explore the feasibility and histological basis of pancreatic two-dimensional shear wave elastography (2D-SWE) measurement in predicting post-operative pancreatic fistula (POPF) following partial pancreatectomy and to build a prediction model by pre-operative features.</p> Methods <p>305 pancreatic or periampullary disease patients were enrolled, divided into a training (<i>n</i> = 203) and a validation group (<i>n</i> = 102). POPF was graded as A (or the so-called “biochemical leak”), B, and C. Spearman correlation analysis assessed the histological basis of 2D-SWE measurement value’s (Emean’s) relationship with POPF grades. Multivariate logistic regression analyzed risk factors of POPF occurrence in the training group, and a predictive model was built. The discrimination ability of the model to differentiate POPF grades was analyzed by the area under the receiver operating characteristic curve (AUC).</p> Results <p>Emean could discriminate between the occurrence and grades of POPF (all AUC &gt; 0.75, <i>p &lt;</i> 0.050). Pancreatic fibrosis and acinar atrophy correlated with both Emean and POPF (all <i>p &lt;</i> 0.050). The higher BMI (<i>p</i> = 0.002), non-dilated pancreatic duct (<i>p</i> = 0.001), and lower Emean (<i>p &lt;</i> 0.001) were the independent risk factors of POPF occurrence and could help discriminate the occurrence of different grades of POPF in both groups (all AUC &gt; 0.80, <i>p &lt;</i> 0.050).</p> Conclusions <p>Lower pancreatic 2D-SWE measurements indicated a higher risk of POPF, and the histological basis may lie in 2D-SWE’s correlation with pancreatic fibrosis and acinar atrophy. A model integrating pancreatic 2D-SWE measurements, BMI, and the presence of pancreatic duct dilation could predict POPF risk across varying severity levels.</p>