Liver cancer is common worldwide and associated with relatively high mortality. Sorafenib is a first-line treatment for advanced liver cancer, but its efficacy is limited by its high toxicity, wide distribution in the body and low water solubility. Combination therapy with multiple drugs can lead to greater therapeutic efficacy, and nano-delivery systems can facilitate such therapy by solubilizing drugs and thereby increasing their bioavailability. Here nanoparticles of sorafenib and emodin encapsulated in the copolymer PEG-PLGA were constructed for liver therapy. Nanoparticles carrying sorafenib and emodin were prepared using a double emulsion method, and showed a diameter around 290 nm and uniform morphology. The encapsulation rates of sorafenib and emodin were 77.4 ± 0.71% and 80.78 ± 0.05%, the drug loading rates were 12.0 ± 0.1% and 13.0 ± 0.21%, and the cumulative drug release rates in pH 5.0 medium were 83.6% and 80.2%. The dual-loaded nanoparticles demonstrated significantly suppressed cellular proliferation and markedly enhanced apoptotic induction compared to free drug formulations or monotherapy nanoparticles. In murine xenograft models, the nanoparticles achieved superior tumor growth suppression (p < 0.01 vs free drugs). These findings collectively indicate that the sorafenib-emodin co-encapsulated PEG-PLGA nanoparticles represent a promising therapeutic platform for hepatocellular carcinoma intervention and may provide more therapeutic options against advanced liver cancer.