Tyrosine kinase inhibitors (TKIs) are such as sorafenib the first-line therapeutic drugs for patients with advanced hepatocellular carcinoma. However, patients with TKI-resistant advanced liver cancer are insensitive to TKI treatment, resulting in limited survival benefits. This paper comprehensively reviewed the mechanisms underlying TKI resistance in hepatocytes, investigating activation of tumor signaling pathways, epigenetic regulation, tumor microenvironment, and metabolic reprogramming. Based on resistance mechanisms, it also reviews preclinical and clinical studies of drug resistance strategies and summarizes targeted therapy combined with immunotherapy currently in investigational clinical trials. Understanding the interactions and clinical studies of these resistance mechanisms offers new hope for improving and prolonging patient survival.