Objective: The aim of this study was to assess the therapeutic effects of Jianpi Liqi decoction (JPLQD) in hepatocellular carcinoma (HCC) and explore its underlying mechanisms. Methods: The characteristics and outcomes of HCC patients with intermediate stage B who underwent sequential conventional transcatheter arterial chemoembolization (cTACE) and radiofrequency ablation (RFA) only or in conjunction with JPLQD were analysed retrospectively. The plasma proteins were screened using label-free quantitative proteomics analysis. The effective mechanisms of JPLQD were predicted through network pharmacology approach and partially verified by ELISA. Results: Clinical research demonstrated that the Karnofsky Performance Status (KPS), traditional Chinese medicine (TCM) syndrome scores, neutropenia and bilirubin, median progression-free survival (PFS), and median overall survival (OS) in HCC patients treated with JPLQD were superior to those in patients not treated with JPLQD (all P<0.05). The analysis of network pharmacology, combined with proteomics, suggested that 52 compounds targeted 80 potential targets, which were involved in the regulation of multiple signaling pathways, especially affecting the apoptosis-related pathways including TNF, p53, PI3K-AKT, and MAPK. Plasma IGFBP3 and CA2 were significantly up-regulated in HCC patients with sequential cTACE and RFA therapy treated with JPLQD than those in patients not treated with JPLQD (P<0.001). The AUC of the IGFBP3 and CA2 panel, estimated using ROC analysis for JPLQD efficacy evaluation, was 0.867. Conclusion: These data suggested that JPLQD improves the quality of life, prolongs the overall survival, protects liver function in HCC patients, and exhibits an anticancer activity against HCC. IGFBP3 and CA2 panels may be potential therapeutic targets and indicators in the efficacy evaluation for JPLQD treatment, and the effective mechanihsms involved in the regulation of multiple signaling pathways, possibly affected the regulation of apoptosis.