Liver cancer is one of the most common cancers worldwide and is also one of the most difficult cancers to treat, resulting in almost one million deaths per year, and the danger of this cancer is compounded when the tumor is nonresectable. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and has the third highest mortality rate worldwide. Considering the morbid statistics surrounding this cancer it is a popular research topic to target for better therapy practices. This review summarizes the role of nanotechnology in these endeavors. Nanoparticles (NPs) are a very broad class of material and many different kinds have been used to potentially combat liver cancer. Gold, silver, platinum, metal oxide, calcium, and selenium NPs as well as less common materials are all inorganic NPs that have been used as a therapeutic, carrier, or imaging agent in drug delivery systems (DDS) and these efforts are described. Carbon-based NPs, including polymeric, polysaccharide, and lipid NPs as well as carbon dots, have also been widely studied for this purpose and the role they play in DDS for the treatment of liver cancer is illustrated in this review. The multifunctional nature of many NPs described herein, allows these systems to display high anticancer activity in vitro and in vivo and highlights the advantage of and need for combinatorial therapy in treating this difficult cancer. These works are summarized, and future directions are presented for this promising field.