This study investigates effects of St. John's wort on cognition, Aβ levels, and microglial activation. Past studies have shown hyperforin, the main active constituent of St. John's wort, modulates the phagocytic activity of microglia. Other investigations indicate that hyperforin affects memory-enhancing properties in rodents. Hyperforin is a potent nuclear receptor ligand for PXR that leads to increased expression of the ATP binding cassette (ABC) transporter P glycoprotein, ABCB1, which is an ATP-dependent efflux pump with broad substrate specificity at the human BBB. Additionally, hyperforin inhibited P-glycoprotein transport activity in vitro, and enhanced the export activity of ABCB1 at the blood-brain barrier, and thus, reduce the concentration of intracerebral monomeric Aβ. Several studies have shown that ABCB1 contributes to Aβ clearance in mouse models and cell culture studies. Other studies demonstrated that another ABC transporter (ABCC1) has a strong influence on Aβ pathology in different mouse models. This study tested five extracts of SJW with variable hyperforin concentrations, to elucidate their effects on AD hallmarks and cognition in mice. Results demonstrate that extracts with low to negligible levels of hyperforin significantly improve memory performance and counteract neurodegeneration in vivo in a murine AD model. Oral administration of these extracts is highly effective at decreasing intracerebral Aβ42 levels and reducing Aβ plaques. These extracts do not only activate cerebral macrophages to improve phagocytosis rates by microglia, as confirmed in vitro and in vivo, but they additionally enhance ABCC1 transporter excretion of Aβ. Thus, SJW represents a viable treatment option for AD when special attention is paid to the extraction procedure of the plant material.