This study was designed to investigate the pharmacological effects and mechanisms of polysaccharides from Dendrobium officinal (DOP) on premature ovarian failure (POF) in natural aging mice. Fifteen months old female mice (n  =  28) and young adult female mice (n  =  14, 6 weeks) were used. DOP (70 mg/kg) was administrated to mice by oral gavage for 10 weeks and the protection effects of DOP on ovaries were investigated in vivo. The results showed that DOP reduced body weight, ovary and uterus/body weight parameters to normal level and alleviated ovarian pathological damage. Moreover, DOP could reduce pro-inflammatory cytokines (TNF-α, IL-6) and MDA levels and improve estradiol, SOD, GSH-Px, T-AOC and IL-10 levels in serum. These results suggested that DOP may alleviate the damage caused by aging through the inhibition of the nuclear factor -κB (NF-κB) and p53/Bcl-2-mediate signaling pathways. Moreover, we found that DOP can increase the numbers of mitochondria and endoplasmic reticulum. Moreover, DOP increased the numbers of different stages of follicular cells and improved mitochondrial membrane potential in ovaries. These results indicated that DOP may relieve ovarian damage through the protection of mitochondria in the ovaries. These findings suggest that DOP may be a promising drug for treating POF caused by natural aging in females.