Background: In Alzheimer disease (AD), medications seem to decrease the disease progression but not to treat it. Curcumin has a number of biological applications along with a significant, anti-inflammatory antioxidant activity both invivo and invitro. Also, mesenchymal stem cells (MSCs) tend to provide a hope for a cure, from this aspect we evaluated the effect of mesenchymal stem cells (MSCs) and a novel curcumin derivative (NCD) on AD rat model. Methods: Seventy rats which were divided equally into: control group, AD group, AD group received the NCD, AD group received pure curcumin, AD group received MSCs then NCD, AD group received MSCs, AD group received concomitant MSCs with NCD. Histopathological examination of brain tissues and gene expression of BDNF, TLR4, Bax , bcl2 and Seladin-1 gene expression in brain tissue , estimation of serum IL-10, IL-6 by ELISA, measurement of brain MDA and GSH by colorimetry , detection of VEGF by immunohistochemistry , Estimation of brain cholesterol and behavior study through percent of alternation and time consumed in T-maze test was performed. Results: Histopathological examination of brain tissue from AD animals revealed the presence of plaques. Administration of MSCs or MSCs with NCD improved the histopathological picture with plaque disappearance and improved the behavior study, while other groups showed decrease of plaque formation. Gene expression demonstrated that BDNF, TLR4, bcl2 and Seladin-1 were upregulated while Bax gene was downregulated in all treated groups with significant effect in the group treated with MSCs alone and group treated with both MSCs and NCD. Levels of IL-10 were increased while of IL-6 were decreased in all treated groups. MDA and cholesterol levels were decreased while GSH levels were increased in all treated groups. Conclusion: Administration of BM-derived MSCs either alone or with the NCD exerts a therapeutic effect on the brain lesion in Alzheimer's disease. This effect may be through the anti-inflammatory, antioxidant and antiapoptotic action of both MSCs and curcumin.