Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death in people, and a common primary liver cancer. Lacking early diagnosis and a high recurrence rate after surgical resection, systemic treatment is still an important treatment method for advanced HCC. Different drugs have distinct curative effects, side effects and drug resistance due to different properties. At present, conventional molecular drugs for HCC have displayed some limitations, such as adverse drug reactions, insensitivity to some medicines, and drug resistance. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), have been well documented to be involved in the occurrence and progression of cancer. Novel biomarkers and therapeutic targets, as well as research into the molecular basis of drug resistance, are urgently needed for the management of HCC. We review current research on ncRNAs and consolidate the known roles regulating drug resistance in HCC and examine the potential clinical applications of ncRNAs in overcoming drug resistance barriers in HCC based on targeted therapy, cell cycle non-specific chemotherapy and cell cycle specific chemotherapy.