Background: Alzheimer's disease (AD) is a progressive neuropsychiatric disorder that causes dementia. It mostly affects people older than 65 years. The exact mechanisms of AD are not fully understood but affection of apoptosis, oxidative stress and neuroinflammation may be contributing factors. Aim: To evaluate the ability of sitagliptin and/or calcipotriol to attenuate lipopolysaccharide (LPS)-induced AD in mice and to elucidate their possible mechanisms of action. Methods: Sixty male Balb/c mice were divided into 6 equal groups: Control; LPS; LPS + carboxymethyl cellulose; LPS + Sitagliptin; LPS + Calcipotriol; and LPS + Sitagliptin + Calcipotriol group. Behavioral tests, tissue catalase (CAT), superoxide dismutse (SOD) and thiobarbituric acid derivatives (TBARS) were assessed. Also, tissue transforming growth factor beta-1 (TGF-β1), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were determined. Parts of the hippocampus were subjected to histopathological, immunohistochemical and electron microscopic examination. Results: Administration of sitagliptin and/or calcipotriol prior to LPS injection induced significant increase in the recognition index, tissue CAT and SOD associated with significant decrease in tissue TBARS, TNF-α, IL-6 and TGF-β1 and significant improvement of the histopathological, immunohistochemical and electron microscopic picture compared to LPS group. These changes were significant in sitagliptin/calcipotriol combination group compared to the use of each of these drugs alone. Conclusion: Sitagliptin/calcipotriol combination might represent a new therapeutic modality for amelioration of Alzheimer's disease.