Liver cancer is classified amongst the foremost causes of tumor-associated deaths around the world. The liver cancer death is more common in men compared to females with overall death rate being doubled from 1980-2017. A primary pathological category of liver cancer is the hepatocellular carcinoma (HCC), which accounts for nearly 80% of all liver cancers. Since HCC is mainly diagnosed at advanced stages, making the surgical and locoregional treatments extremely difficult. Dysregulation of transcription factors, the central modulators of normal and transformed tumorous cellular processes such as STAT-1, STAT-3, NF-κB, Ap1, and HIF-1α are known to be activated in HCC invasion, progression, and metastasis are highlighted in this review. The recently approved drugs, such as sorafenib regorafenib, lenvatinib, and cabozantinib, are tyrosine kinase inhibitors (TKIs), which completely reduce HCC progression by targeting transcription factors are discussed.