Neurogenesis continues throughout the lifetime in the hippocampus, while the rate declines with brain aging. It has been hypothesized that reduced neurogenesis may contribute to age-related cognitive impairment. Ginsenoside Rg1 is an active ingredient of Panax ginseng in traditional Chinese medicine, which exerts anti-oxidative and anti-aging effects. This study explores the neuroprotective effect of ginsenoside Rg1 on the hippocampus of the D-gal (D-galactose) induced aging rat model. Sub-acute aging was induced in male SD rats by subcutaneous injection of D-gal (120 mg/kg·d) for 42 days, and the rats were treated with ginsenoside Rg1 (20 mg/kg·d, intraperitoneally) or normal saline for 28 days after 14 days of D-gal injection. In another group, normal male SD rats were treated with ginsenoside Rg1 alone (20 mg/kg·d, intraperitoneally) for 28 days. It showed that administration of ginsenoside Rg1 significantly attenuated all the D-gal-induced changes in the hippocampus, including cognitive capacity, senescence-related markers and hippocampal neurogenesis, compared with the D-gal-treated rats. Further investigation showed that ginsenoside Rg1 protected NSCs/NPCs (neural stem cells/progenitor cells) shown by increased level of SOX-2 expression; reduced astrocytes activation shown by decrease level of Aeg-1 expression; increased the hippocampal cell proliferation; enhanced the activity of the antioxidant enzymes GSH-Px (glutathione peroxidase) and SOD (Superoxide Dismutase); decreased the levels of IL-1β, IL-6 and TNF-α, which are the proinflammatory cytokines; increased the telomere lengths and telomerase activity; and down-regulated the mRNA expression of cellular senescence associated genes p53, p21Cip1/Waf1 and p19Arf in the hippocampus of aged rats. Our data provides evidence that ginsenoside Rg1 can improve cognitive ability, protect NSCs/NPCs and promote neurogenesis by enhancing the antioxidant and anti-inflammatory capacity in the hippocampus.