Heat stroke-induced death is a major killer worldwide. Mice were subjected to acute heat stress by exposing them to whole-body hyperthermia (WBH) treatment and were used as a model to study heat stroke. Administration of L-arginine (L-arg, 120 mg/kg, i.p) 2 h after the cessation of WBH rescued the mice from heat-induced death and reduced the hypothermia. Heat shock protein 70 levels in the liver were increased significantly in heat-stressed mice administered L-arg compared with the heat-stressed group. WBH induced apoptosis, as indicated by DNA fragmentation, and increased levels of p53 and caspase-3 activity, which were significantly reduced by the administration of L-arg. The levels of inducible nitric oxide synthase in the liver, nitrite, and inflammatory cytokines like interleukin 1beta and tumor necrosis factor-alpha in the serum increased in WBH-treated mice. The levels of the above markers of heat stress significantly decreased in L-arg-treated mice. Kinin-B1 receptor (kinin-B1R) in cardiac tissue that is upregulated in heat stressed mice was significantly lower in L-arg-administered mice. These data suggest the potential use of L-arg, a nonessential amino acid that is used as an enteral diet supplement, to treat heat stroke-related injury when administered at the appropriate dose and time.