Ten new polyprenylated tetraoxygenated xanthones, monogxanthones A-J (1-10), together with eight known analogues (4b, 11-17) were identified from the roots of Hypericum monogynum. The structures of these new polyprenylated xanthones (1-10), a class of compounds rarely found in plants of the genus Hypericum, were elucidated by the interpretation of their HRESIMS, 1D and 2D NMR, and electronic circular dichroism data. Compounds 1 and 2 exhibited neuroprotective effects against corticosterone (Cort)-induced lesions of PC12 cells at concentrations of 6.25, 12.50, and 25.00 μM, with cell viability greater than 75%, as well as inhibitory effects on nitric oxide production in lipopolysaccharide-induced BV2 microglia cells, with IC50 values of 7.47 ± 0.65 and 9.60 ± 0.12 μM, respectively. Collectively, these results shed new light on the potential of polyprenylated xanthones from the genus Hypericum in the development of antidepression therapies.