Acetaminophen (paracetamol, APAP) has a worldwide usage. Nevertheless, overdosing may induce severe toxicity. Dexpanthenol (DXP) is the alcohol provitamin form of vitamin B5 with antiinflammatory and antioxidant efficacy. In the present study, the biochemical and histological protective effects of DXP against acetaminophen-induced oxidative hepatorenal damage were examined. Rats were divided into the following groups: healthy control (HG); APAP (AG (APAP Group), 1500 mg/kg, orally); DXP (DXG, 500 mg/kg, intraperitoneally); APAP+N-acetylcysteine (NAC) (ANG, 100 mg/kg, intraperitoneally); APAP+DXP (ADXG) and APAP+NAC+DXP (ANDXG) groups. Liver and kidney function tests, oxidant/antioxidant parameters and histological assessment were performed. In the AG group, marked hepatorenal damage occurred with the significant elevation of kidney (urea and creatinine) and liver (alanine aminotransaminase, aspartate aminotransaminase lactate dehydrogenase) function tests, and oxidative stress markers such as malondialdehyde, myeloperoxidase and nitric oxide when compared with the HG group (p<0.05). Concurrently, an apparent decrease in catalase and glutathione levels was determined in the AG group (p<0.05). In the ADXG group, DXP significantly decreased oxidant levels in both liver and kidney tissues while increasing the antioxidant levels when compared with the AG group (p<0.05). The resultant histological changes were improved and almost normal organ structures in the ADXG group. Furthermore, the biochemical and histological assessment results revealed that DXP has nearly the same hepatoprotective efficacy with NAC. In renal tissues, when all groups were compared against the AG group, there was a statistically significant difference between all groups (p<0.001) except the ANG group. The histological sections of the ANG group were nearly the same, with the AG group indicating the inadequate nephroprotective effect of NAC. In the light of these findings, we think that DXP may be used in daily clinical practice of acute hepatorenal APAP-induced toxicity. However, further studies are needed to illuminate its efficacy.