Pyogenic liver abscess (PLA) is a severe condition that significantly increases the risk of sepsis. However, there is a notable dearth of research regarding the prediction of sepsis in PLA patients. The objective of this study was to develop and validate a prognostic nomogram for predicting sepsis in PLA patients. A total of 206 PLA patients were enrolled in our study, out of which 60 individuals (29.1%) met the Sepsis-3 criteria. Independent risk factors for sepsis were identified through univariate and multivariate logistic regression analyses. Subsequently, a nomogram was developed based on age, positive blood culture, procalcitonin, alanine aminotransferase, blood urea nitrogen, andd-dimer. The nomogram demonstrated excellent calibration and discrimination, as evidenced by the area under the receiver operating characteristic curve (AUC) values of 0.946 (95% confidence interval [CI], 0.912–0.979) and 0.980 (95%CI 0.951–1.000) in the derivation and validation cohorts, respectively. Furthermore, decision-curve analysis confirmed the clinical utility of the nomogram. This study provides valuable insights for the prevention of sepsis in PLA patients and underscores the potential application of the prognostic nomogram in clinical practice.