Abstract: Objective To evaluate the diagnostic value of CT, MRI and contrast-enhanced ultrasound (CEUS), alone and in combination, in differentiating benign and malignant focal liver lesions (FLL). Methods A total of 130 patients with FLL who were diagnosed and treated at the Affiliated Hospital of Xuzhou Medical University between January 2022 and May 2024 were enrolled. Pathological results were used as the gold standard. Receiver operating characteristic (ROC) curves were plotted to assess the value of CT, MRI, CEUS, and their combined application in differentiating benign and malignant FLL. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of each imaging modality were compared. Results Pathological examination confirmed 69 cases (53.1%) of benign lesions and 61 cases (46.9%) of malignant lesions. ROC curve analysis showed that the areas under the curve (AUCs) for CT, MRI, CEUS, and the combined application in differentiating benign and malignant FLL were 0.775, 0.901, 0.822, and 0.924, respectively. DeLong tests demonstrated that the diagnostic performance of MRI and the combined application was superior to that of CT and CEUS (P<0.05). The combined application showed the highest diagnostic efficiency, although the difference compared with MRI alone was not statistically significant. Significant differences were observed among the imaging modalities in terms of sensitivity, negative predictive value, and accuracy (P<0.05). The combined application achieved the optimal performance for these three indicators, with a sensitivity of 93.44%, a negative predictive value of 94.03%, and an overall diagnostic accuracy of 92.31%. The sensitivities of MRI and the combined application were both significantly higher than those of CT and CEUS (P<0.05). Regarding negative predictive value, MRI and the combined application were superior to CT, and the combined application was also superior to CEUS (P<0.05). In terms of diagnostic accuracy, MRI and the combined application outperformed CT, with the combined application showing the highest accuracy. No statistically significant differences were observed among the imaging modalities with respect to specificity or positive predictive value (P>0.05). Conclusions The combined application of CT, MRI, and CEUS can significantly improve the diagnostic performance in differentiating benign and malignant FLL. MRI alone demonstrates high diagnostic value, while the combined approach offers advantages in negative predictive value and overall diagnostic accuracy.