Vascular dementia is considered a vascular cognitive impairment disease caused by neuronal degeneration in the brain. Several studies have supported the hypothesis that oxidative stress and endothelial dysfunction are the main pathogenic factors in vascular dementia. This current study aims to determine the possible neuroprotective effects of zafirlukast, piracetam and the combination of piracetam and zafirlukast on L‐methionine‐induced vascular dementia in rats. Male Wistar albino rats were divided into five groups. Group I was the normal control, and group II received L‐methionine (1700 mg/kg, P.O.) for 32 days. The remaining groups received zafirlukast (20 mg/kg, P.O.), piracetam (600 mg/kg, P.O.) or their combination (zafirlukast 20 mg/kg + piracetam 600 mg/kg, P.O.) for 32 days after L‐methionine administration. Afterwards, the cognitive and memory performances of the rats were investigated using the novel object recognition (NOR) test; rats were then sacrificed for histopathological and biochemical analyses. L‐methionine‐induced vascular dementia altered rats’ behaviours and the brain contents of different neurotransmitters and acetylcholinesterase activity while increasing levels of oxidative stress and causing notable histopathological alterations in brain tissues. The treatment of vascular dementia with zafirlukast and the combination improved neurochemical, behavioural and histological alterations to a comparable level to those of piracetam. Thus, zafirlukast, piracetam and the combination of both drugs can be considered as potential therapeutic strategies for the treatment of vascular dementia induced by L‐methionine. To the best of our knowledge, this study is the first to explore the neuroprotective effects of zafirlukast and piracetam on L‐methionine‐induced vascular dementia.