The aim of this study was to predict tyrosine kinase inhibitors (TKI) plus anti-PD-1 antibodies (TKI-PD-1) efficacy as second-line treatment in advanced hepatocellular carcinoma (HCC) using radiomics analysis. From November 2018 to November 2019, a total of 55 patients were included. Radiomic features were obtained from the CT images before treatment and filtered using intraclass correlation coefficients (ICCs) and least absolute shrinkage and selection operator (LASSO) methods. Subsequently, ten prediction algorithms were developed and validated based on radiomic characteristics. The accuracy of the constructed model was measured through area under the receiver operating characteristic curve (AUC) analysis; survival analysis was performed via Kaplan–Meier and Cox regression analyses. Overall, 18 (32.7%) out of 55 patients had progressive disease. Through ICCs and LASSO, ten radiomic features were entered into the algorithm construction and validation. Ten machine learning algorithms showed different accuracies, with the support vector machine (SVM) model having the highest AUC value of 0.933 in the training cohort and 0.792 in the testing cohort. The radiomic features were associated with overall survival. In conclsion, the SVM algorithm is a useful method to predict TKI-PD-1 efficacy in patients with advanced HCC using images taken prior to treatment.