Andrographolide is a major bioactive constituent of Andrographis paniculata that has been shown in vitro to have antiviral activity against a number of viruses, including the mosquito transmitted dengue virus (DENV). However, how andrographolide exerts an anti-DENV effect remains unclear. This study therefore sought to further understand the mechanism of action of andrographolide in inhibiting DENV infection of liver cells using a proteomic based approach. Both 1 dimension (D) and 2D proteome systems were used. Initial data was generated through andrographolide treatment of HepG2 cells without DENV infection (1D analysis), while subsequent data was generated through a combination of andrographolide treatment and DENV infection (2D analysis). A total of 17 (1D) and 18 (2D) proteins were identified as differentially regulated. The analyses identified proteins involved in chaperone activities, as well as energy production. In particular evidence suggested an important role for GRP78 and the unfolded protein response in mediating the anti-DENV activity of andrographolide, which might, in part, explain the broad antiviral activity of andrographolide.