Humans are primarily exposed to fluoride (Fl), a widespread environmental pollutant, via contaminated drinking water and foodstuffs. The aim of this study was to examine whether sodium fluoride (NaF) exerted cytotoxic effects in human hepatocarcinoma (HepG2) cells. HepG2 cells were incubated with different concentrations of NaF and reactive oxygen species (ROS) levels, cell cycle, apoptosis, and DNA damage determined. Concentration-dependent studies showed that exposure to HepG2 cells with different concentrations of NaF for 24 hr significantly decreased cell viability and intracellular antioxidant capacity. Furthermore, NaF exposure increased lipid peroxidation levels and accumulation of intracellular ROS; and lowered antioxidant glutathione concentrations. In addition to oxidative impairments, NaF treatment enhanced HepG2 cell death via apoptotic pathway as evidenced by DNA fragmentation and cell cycle arrest. Sodium fluoride treatment unregulated p53 level, and Bax and Bcl2 expression. Diminished cell viability and changes in cell cycle accompanied a rise in p53 expression.