: Liver cancer ranks among the leading causes of cancer-related mortality, necessitating the development of novel diagnostic methods. Deregulated lipid metabolism, a hallmark of hepatocarcinogenesis, offers compelling prospects for biomarker identification. This study aims to employ explainable artificial intelligence (XAI) to identify lipidomic biomarkers for liver cancer and to develop a robust predictive model for early diagnosis. : This study included 219 patients diagnosed with liver cancer and 219 healthy controls. Serum samples underwent untargeted lipidomic analysis with LC-QTOF-MS. Lipidomic data underwent univariate and multivariate analyses, including fold change (FC), -tests, PLS-DA, and Elastic Network feature selection, to identify significant biomarker candidate lipids. Machine learning models (AdaBoost, Random Forest, Gradient Boosting) were developed and evaluated utilizing these biomarkers to differentiate liver cancer. The AUC metric was employed to identify the optimal predictive model, whereas SHAP was utilized to achieve interpretability of the model's predictive decisions. : Notable alterations in lipid profiles were observed: decreased sphingomyelins (SM d39:2, SM d41:2) and increased fatty acids (FA 14:1, FA 22:2) and phosphatidylcholines (PC 34:1, PC 32:1). AdaBoost exhibited a superior classification performance, achieving an AUC of 0.875. SHAP identified PC 40:4 as the most efficacious lipid for model predictions. The SM d41:2 and SM d36:3 lipids were specifically associated with an increased risk of low-onset cancer and elevated levels of the PC 40:4 lipid. : This study demonstrates that untargeted lipidomics, in conjunction with explainable artificial intelligence (XAI) and machine learning, may effectively identify biomarkers for the early detection of liver cancer. The results suggest that alterations in lipid metabolism are crucial to the progression of liver cancer and provide valuable insights for incorporating lipidomics into precision oncology.