Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, continues to be a major global cause of cancer-related mortality. HCC is one of the most difficult malignancies to treat because of its late diagnosis, high recurrence rate, and limited therapeutic options. There is a need for novel therapeutic approaches, including regenerative medicine applications using stem cells and their secretome. This chapter addresses the therapeutic role of mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) in HCC. MSC-derived EVs present a cell-free alternative to whole-cell therapy. These EVs retain the regenerative, immunomodulatory, and antitumor properties of their parent MSCs while offering advantages such as a reduced risk of immune rejection. MSCs, however, have displayed a dual role in promoting and inhibiting cancer. Consequently, the contents of their EVs must be thoroughly examined to ascertain their precise role and potential in cancer therapy. The chapter examines the intricate molecular processes by which MSC-EVs exert their biological action in cancer. The potential of EVs as therapeutic agents in a range of malignancies and as drug delivery systems, will be covered. The chapter also highlights the promises, challenges, and future directions in developing EV-based treatment approaches for HCC.