Purpose <p>This study aims to analyze the characteristics of non-specific uptake(NSU) of ⁶⁸Ga-FAPI in the pancreas and explore potential independent factors associated with its presence on ⁶⁸Ga-FAPI PET/CT images.</p> Materials <p>This retrospective study included 122 patients who underwent ⁶⁸Ga-FAPI PET/CT examinations for stage and re-stage of abdominal malignant tumor, dividing patients with pancreatic NSU and patients without pancreatic NSU. Patients with clinical evidence of pancreatitis or pancreas tumor were excluded. Univariate and multivariate regression analysis were used to identify factors associated with pancreatic NSU. ROC curve analysis was used to evaluate optimal cut-off for the presence of pancreatic NSU.</p> Results <p>A total of 122 patients were included in the final analysis, comprising 42 patients with pancreatic NSU and 80 patients without NSU. The SUVmax was 7.94 ± 5.39 and 2.01 ± 0.50 in NSU and non-NSU group respectively on ⁶⁸Ga-FAPI PET/CT. Univariate and multivariate regression analysis identified independent risk factors associated with pancreatic NSU, including diabetes (OR: 6.894, 95% CI: 1.208–39.331, <i>P</i> = 0.03), hematocrit (OR: 0.858, 95% CI: 0.749–0.983, <i>P</i> = 0.027), and CRP (OR: 1.029, 95% CI: 1.009–1.049, <i>P</i> = 0.005). ROC curve analysis determined the optimal cut-off of 17.85 and 37.5 for CRP and hematocrit in predicting NSU in the pancreas on ⁶⁸Ga-FAPI PET/CT imaging.</p> Conclusion <p>Pancreatic diffuse NSU is associated with the presence of diabetes, lower hematocrit levels, and higher CRP levels. These findings may assist clinicians and nuclear medicine physicians in interpreting imaging appearances, helping to avoid misdiagnosis.</p>