Nandrolone decanoate is a synthetic anabolic steroid used by both athletes and non-athletes extensively, especially in combination with nicotine in smokers. The goal of the current study was to investigate the neurochemical and behavioral alterations of nandrolone decanoate combined with nicotine and the potential modulation effect of grape seed extract. Rats were daily treated with nandrolone (Nan 15 mg/kg s.c), nicotine (Nic 0.75 mg/kg, i.p.), grape seed extract (GSE 100 mg/kg, i.p.), Nan/Nic, Nan/Nic/GSE 50 mg/kg or Nan/Nic/GSE 100 mg/kg in combination for 14 days. Oxidative stress biomarkers (malondialdehyde, glutathione and nitric oxide), peroxisome proliferator-activated receptor alpha and acetylcholinesterase in brain homogenate were measured. Open field, defensive aggression, irritability, novel object recognition paradigms and brain histopathology were done. The control group received arachis oil subcutaneously and i.p. saline. Nandrolone alone increased anxiety, defensive aggression, and irritability compared to the normal group. Exposure to Nic increased locomotion, rearing, and defensive aggression compared to the normal group. When Nan/Nic were given together they had no significant effect on locomotion, rearing, or anxiety compared with the normal group. In contrast, defensive aggression and irritability increased with the Nan/Nic combination. Memory performance (object recognition) was decreased by Nan and Nan/Nic coadministration yet increased after Nic treatment. Grape seed treatment especially the high dose normalized irritability and defensive aggression in comparison to the Nan/Nic group. Nandrolone or Nic being given alone or in combination significantly increased lipid peroxidation of the brain (malondialdehyde) and nitric oxide, while decreased reduced glutathione and peroxisome proliferator-activated receptor alpha (PPAR-α) levels were decreased. These biochemical alterations were markedly alleviated by treatment with GSE. In addition, degenerated neurons were observed in the brains of the Nan, Nic or Nan/Nic groups but not in the Nan/Nic/GSE combination groups. Our results suggest that GSE can modulate the behavioral, biochemical, and histopathological alterations in rats exposed to nandrolone and nicotine.