Toll-like receptor 4 (TLR4) appears to play an important role in the development and progression of hepatocellular carcinoma (HCC), but it is unclear whether single-nucleotide polymorphisms (SNPs) in the TLR4 gene influence HCC. In this study, we investigated the effects of TLR4 SNPs on HepG2 cell survival and proliferation, migration, and invasion. Plasmids carrying wild-type or mutant versions of the TLR4 gene (A896G and/or C1196T) were stably transfected into HepG2 cells, and cell viability and proliferation were analyzed using the Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays, whereas apoptosis was assessed using flow cytometry. Migration and invasion were measured in a transwell chamber assay, and expression of inflammatory cytokines and downstream effectors was examined using real-time PCR and western blotting. Specific inhibitors of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), or phosphatidylinositol 3-kinase (PI3K) were added to the HepG2 cultures to explore the potential role of each pathway in TLR4 signaling. TLR4 SNPs did not affect expression levels in transfected cells. Compared with wild-type TLR4, mutant TLR4 was associated with lower cell proliferation, migration, invasion, and apoptotic threshold. In addition, the mutations were associated with significantly lower expression of nuclear factor κB (NF-κB), IL-6, and TGF-β1, even after stimulation with lipopolysaccharide. The expression of p-Akt was similar in the presence of wild-type or mutant TLR4. The 896G and 1196T SNPs in the TLR4 gene are associated with reduced TLR4-mediated signaling and, therefore, with lower survival, proliferation, and metastasis in HepG2 cells.