Objectives To determine whether inhibition of kinase signaling will suppress resistin-induced liver cancer progression. Resistin is located in monocytes and macrophages of adipose tissue. This adipocytokine is an important link between obesity, inflammation, insulin resistance, and cancer risk. Pathways that resistin is known to be involved include but are not limited to mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinases (ERK). The ERK pathway promotes cellular proliferation, migration, survival of cancer cells, and tumor progression. The Akt pathway is known to be up-regulated in many cancers including liver cancer. Methods Using an in vitro model, HepG2 and SNU-449 liver cancer cells were exposed to resistin ± ERK, Akt, or both inhibitors. The following physiological parameters were assessed: cellular proliferation, ROS, lipogenesis, invasion, MMP, and lactate dehydrogenase activity. Results The inhibition of kinase signaling suppressed resistin-induced invasion and lactate dehydrogenase in both cell lines. In addition, in SNU-449 cells, resistin increased proliferation, ROS, and MMP-9 activity. Inhibition of PI3K and ERK decreased phosphorylated Akt and ERK, and pyruvate dehydrogenase. Conclusions In this study, we describe the effect of Akt and ERK inhibitors to determine if inhibition suppresses resistin-induced liver cancer progression. Resistin promotes cellular proliferation, ROS, MMP, invasion and LDH activity in SNU-449 liver cancer cells which is differentially mediated by Akt and ERK signaling pathways.