Selenium is a micronutrient that had been suggested to reduce the risk of cancer. Hepatocellular carcinoma (HCC), a prevalent disease and one of the most lethal cancers in the world, awaits new alternative treatment strategies to improve patients’ survival. As an essential trace element, selenium has been studied for its anticancer properties in both oxidative stress and inflammatory-related mechanisms that may contribute to HCC growth and metastasis. In recent decades, increasing studies have investigated the potential role of selenium in liver cancer involving several major cancer-associated signaling pathways, metabolic pathways, and antioxidant defense systems both in vitro and in preclinical models. It was also observed that there was an increase in the trend of development of novel selenium nanoparticles and selenium-containing inhibitors aiming to improve the therapeutic efficacy and relative potency of selenium. However, controversies remain with whether a relationship exists between serum selenium level and HCC risk. This chapter aims to summarize the multi-target and multi-pathway in vitro and in vivo pharmacological effects of selenium in HCC, to provide a more comprehensive view and to highlight the recently discovered molecular mechanisms We hope this chapter could outline the correlation of selenium level and the risk of HCC in patients and discuss the clinical application of selenium in HCC prevention and treatment.