Alzheimer’s disease (AD) is the most prevalent cause of dementia; microglia have been implicated in AD pathogenesis, but their role is still matter of debate. Our study showed that single systemic wild-type (WT) hematopoietic stem and progenitor cell (HSPC) transplantation rescued the AD phenotype in 5xFAD mice and that transplantation may prevent microglia activation. Indeed, complete prevention of memory loss and neurocognitive impairment and decrease of β-amyloid plaques in the hippocampus and cortex were observed in the WT HSPC-transplanted 5xFAD mice compared with untreated 5xFAD mice and with mice transplanted with 5xFAD HSPCs. Neuroinflammation was also significantly reduced. Transcriptomic analysis revealed a significant decrease in gene expression related to “disease-associated microglia” in the cortex and “neurodegeneration-associated endothelial cells” in the hippocampus of the WT HSPC-transplanted 5xFAD mice compared with diseased controls. This work shows that HSPC transplant has the potential to prevent AD-associated complications and represents a promising therapeutic avenue for this disease. Display omitted •WT HSPC transplantation rescues memory and neurocognitive decline•WT HSPC transplantation reduces Aβ plaque density and partially preserves blood-brain integrity•WT HSPC transplantation may prevent microgliosis and neuroinflammation Mishra et al. demonstrate that single systemic wild-type hematopoietic stem and progenitor cell transplantation leads to complete preservation of the neurocognitive performance, partial preservation of blood-brain barrier integrity, and reduction of the Aβ plaque, microgliosis, and neuroinflammation in 5xFAD mice. In contrast, 5xFAD HSPC transplantation has no to limited impact.