Demethylcantharidin (DEM) is a commonly used antitumor drug, but its effectiveness is hindered by poor tumor targeting and significant organ toxicity. This study aimed to develop an innovative drug delivery system to enhance the delivery of DEM. Nanoemulsion-based lipid nanoparticles (DNLNs) were created by encapsulating nanoemulsions into lipid nanoparticles. We assessed cell proliferation, apoptosis, cell cycle, and nanoparticle uptake using Cell Counting Kit-8 (CCK-8), flow cytometry, and in situ fluorescence assays. The H22 tumor-bearing mouse model was used to evaluate the antitumor efficacy, organ toxicity, and distribution of DNLNs. Results showed that DNLNs significantly inhibited H22 cell proliferation and promoted apoptosis, with enhanced cellular uptake of DNLNs. Compared to DEM alone, DNLNs demonstrated improved tumor targeting, increasing the tumor inhibition rate by 23.24%. Additionally, DNLNs improved white blood cell counts and reduced organ toxicity. This study highlights the potential of nanoemulsion-based lipid nanoparticles for more effective delivery of DEM in liver cancer treatment.