The transition metals iron (Fe) and copper (Cu) are needed at low levels for normal health and at higher levels they become toxic for humans and animals. The acute liver toxicity of Fe and Cu was studied in Sprague Dawley male rats (200g) that received ip 0–60mg/kg FeCl2 or 0–30mg/kg CuSO4. Dose and time-responses were determined for spontaneous in situ liver chemiluminescence, phospholipid lipoperoxidation, protein oxidation and lipid soluble antioxidants. The doses linearly defined the tissue content of both metals. Liver chemiluminescence increased 4 times and 2 times after Fe and Cu overloads, with half maximal responses at contents (C50%) of 110μgFe/g and 42μgCu/g liver, and with half maximal time responses (t1/2) of 4h for both metals. Phospholipid peroxidation increased 4 and 1.8 times with C50% of 118μg Fe/g and 45μg Cu/g and with t1/2 of 7h and 8h. Protein oxidation increased 1.6 times for Fe with C50% at 113μg Fe/g and 1.2 times for Cu with 50μg Cu/g and t1/2 of 4h and 5h respectively. The accumulation of Fe and Cu in liver enhanced the rate of free radical reactions and produced oxidative damage. A similar free radical‐mediated process, through the formation HO• and RO• by a Fenton-like homolytic scission of H2O2 and ROOH, seems to operate as the chemical mechanism for the liver toxicity of both metals. The acute liver toxicity of Fe and Cu overloads, evaluated from dose and time-responses, indicate that a similar chemical mechanism of a free radical‐mediated process seems to operate for the biochemical effects through the formation HO• and RO• by a Fenton-like homolytic scission of H2O2 and ROOH. Display omitted ► Liver oxidative damage is produced by higher than normal Fe and Cu liver contents. ► Metal concentration in liver is linearly related to metal intakes. ► Increased liver Fe and Cu contents similarly produced increased oxidative damage. ► This damage is simultaneous and generated for a common biochemical mechanism. ► Free radical process operate by HO• and RO• generated from H2O2 and ROOH scission.