Even though RNA treatments were first proposed as a way to change aberrant signaling in cancer, research in this field is currently ongoing. The term "RNAi" refers to the use of several RNAi technologies, including ribozymes, riboswitches, Aptamers, small interfering RNA (siRNA), antisense oligonucleotides (ASOs), and CRISPR/Cas9 technology. The siRNA therapy has already achieved a remarkable feat by revolutionizing the treatment arena of cancers. Unlike small molecules and antibodies, which need administration every three months or even every two years, RNAi may be given every quarter to attain therapeutic results. In order to overcome complex challenges, delivering siRNAs to the targeted tissues and cells effectively and safely and improving the effectiveness of siRNAs in terms of their action, stability, specificity, and potential adverse consequences are required. In this context, the three primary techniques of siRNA therapies for hepatocellular carcinoma (HCC) are accomplished for inhibiting angiogenesis, decreasing cell proliferation, and promoting apoptosis, are discussed in this review. We also deliberate targeting issues, immunogenic reactions to siRNA therapy, and the difficulties with their intrinsic chemistry and transportation.