Photothermal therapy (PTT) is a recently developed and promising strategy for the treatment of hepatocellular carcinoma (HCC). However, apoptosis has been extensively investigated as the mechanism of the underlying effect of PTT on cancer to date. Here, we explored alternative mechanisms of these therapeutic effects, including the activation of cell-cycle arrest and autophagy during PTT in addition to apoptosis under mild temperature. We treated the HCC cell line HepG2 with polydopamine (PDA)-coated branched Au-Ag nanoparticles at various concentrations along with PTT using an 808-nm laser. Apoptosis was evaluated based on flow cytometry, western blot analysis of apoptosis related proteins (BAX, BCL2, caspase 3), Hoechst staining, and TUNEL staining. To explore the role of autophagy, we treated cells with the autophagy inhibitor chloroquine diphosphate. Enhancement of apoptosis by PTT with nanoparticle treatment was observed after autophagy was inhibited. Moreover, inhibition of autophagy markedly enhance the suppression of tumor growth in vivo in a HepG2 mouse xenograft model. These results suggest that further exploration of the mechanism of PTT can help guide its clinical application, and that autophagy inhibition combined with PTT could be a promising strategy for HCC treatment.