Cancer is a major cause of death worldwide. Hepatocellular carcinoma (HCC) is one of the malignancies with the highest mortality-to-incidence ratio (> 0.9), and in some countries this value is up to 1. Unfortunately, many patients are diagnosed at advanced stages of the disease. Therefore, HCC early markers, as well as novel therapeutic approaches, are urgently needed. HCC is the main type of liver cancer and it is associated with different factors including alcohol use, viral infections, and fatty liver disease. A significant percentage of HCC patients previously had liver cirrhosis. Several ion channels have been proposed as novel potential markers and therapeutic targets for diverse cancers including HCC. Here, we review most of the findings associating ion channel expression with HCC and its etiological factors, as well as some possible pro-tumorigenic mechanisms of action for ion channels in HCC. Novel therapies for HCC treatment and prevention are also discussed. Ion channel targeting offers a plethora of opportunities for HCC prevention, early diagnosis, and therapy that may help to reduce the extremely high mortality-to-incidence ratio of this malignancy.