Transforming growth factor-beta (TGF-β) is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression. Among different ligands of the TGF-β family, TGF-β1 modulates most of its biological outcomes. Despite the abundant expression of TGF-β1 in the liver, steatosis to hepatocellular carcinoma (HCC) progression triggers elevated TGF-β1 levels, contributing to poor prognosis and survival. Additionally, elevated TGF-β1 levels in the tumor microenvironment create an immunosuppressive stage via various mechanisms. TGF-β1 has a prime role as a diagnostic and prognostic biomarker in HCC. Moreover, TGF-β1 is widely studied as a therapeutic target either as monotherapy or combined with immune checkpoint inhibitors. This review provides clinical relevance and up-to-date information regarding the potential of TGF-β1 in diagnosis, prognosis, and therapy against HCC.