Abstract: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide. Due to the asymptomatic nature of early-stage HCC and its high recurrence rate, current clinical treatments are limited in their effectiveness. Long non-coding RNAs (lncRNAs) play a crucial role in the occurrence, development, and prognosis of HCC, making them a potential method and cutting-edge technology for targeted HCC therapy. However, their clinical application is restricted due to factors such as large molecular weight, complex structure, poor stability, and difficulties in in vivo delivery. Nanoparticles (NPs) can protect lncRNA molecules from degradation and enhance therapeutic efficacy through precise targeted delivery, offering a promising new solution for lncRNA-targeted HCC therapy. This review describes the basic mechanisms of using lncRNAs in combination with nanoparticle drug carriers for HCC treatment, summarizes the functions of lncRNAs in HCC, and elaborates on the potential of nanoparticle drug carriers in conjunction with lncRNAs for HCC therapy. Additionally, this review discusses the advantages, challenges, and countermeasures of this combined strategy in the treatment of solid tumors, providing new directions and strategies for developing effective HCC treatment plans.