Background: Oxidative stress is implicated in the pathogenesis of many diseases. Proper management of oxidative stress requires antioxidants from external sources to supplement that of the body. Plants are considered as a major source of antioxidants because of their natural origin and therapeutic benefits. Objectives: This study was aimed at investigating the renoprotective and antioxidant capacity of hydroethanolic extract of Senecio serratuloides (HESS). Materials and Methods: In vitro and ex vivo antioxidant capacity of the extract was investigated. Female Wistar rats were treated with Nw-nitro L-arginine methyl ester (L-NAME) (40 mg/kg) for 4 weeks and then cotreating with L-NAME (20 mg/kg) and extract (HESS150 or HESS300 mg/kg) for 2 weeks and finally with plant extract or normal saline only for 2 weeks making a total of 8 weeks. Twenty-four-hour urine samples were collected during the study, and at the end of the study; blood and kidneys were harvested for biochemical and histological assays. Results: HESS exhibited high antiradical activity against 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radicals with IC50values of 0.1 and 0.4 mg/ml, respectively. HESS significantly (P < 0.01) augmented L-NAME-induced decrease in creatinine clearance, glomerular filtration rate, and serum calcium concentration. HESS significantly increased in vivo antioxidant capacity (P < 0.01), decreased malondialdehyde (P < 0.01), and Bax (P < 0.001) concentration. It showed renoprotection and significantly (P < 0.01) prevented collagen deposition in the kidneys. Conclusion: S. serratuloides has renoprotective and free radical-scavenging properties and therefore maybe important in combating oxidative stress-mediated diseases in the kidneys and other parts of the body.