Display omitted •Stevia residue extract (SRE) is prepared during steviol glycosides production.•Chlorogenic acids and caffeic acid were identified as the major components of SRE.•SRE ameliorated oxidative stress in d-galactose (d-gal) induced aging mice.•SRE promoted the activation of Akt/Nrf2/HO-1 pathway in d-gal treated mice liver.•Dietary intake of SRE may be beneficial in preventing or delaying the onset of aging. The present study investigated the effect of Stevia residue extract (SRE) against oxidative stress in d-galactose (d-gal) induced aging mice. LC-MS/MS analysis revealed that SRE is a good source of chlorogenic acids. Biochemical results showed that SRE significantly increased the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total antioxidant capacity (T-AOC), and decreased acetylcholinesterase (AChE) activity and malondialdehyde (MDA) level in serum, liver or brain of d-gal induced aging mice. At 200 mg/kg, SRE up-regulated the mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target genes including GPx1, CAT, SOD1, quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1) in d-gal treated mice liver. SRE also up-regulated the protein expression of Nrf2, HO-1 and the ratio of phosphorylated Akt to Akt (pAkt/Akt) in d-gal treated mice liver. These findings suggest that SRE is able to protect against oxidative stress in d-gal induced aging model via activation of Akt/Nrf2/HO-1 pathway. In conclusion, SRE may provide a promising dietary approach for the prevention or alleviation of oxidative stress and age-related conditions.