Objective. To evaluate the antioxidant capacity and protective effect of aqueous and hydroalcoholic extracts of Senecio rhizomatus Rusby in rat erythrocytes subjected to oxidative stress with hydrogen peroxide (H2O2). Methodology. This study used an experimental design. The extracts were obtained through maceration with 96° ethanol (SeR96), 70° ethanol (SeR70), 50° ethanol (SeR50) and through infused water (SeRAc). Secondary metabolites were identified through colorimetric reactions and precipitation. In each extract, we could determine the capacity to eliminate 2,2-diphenyl-1-picrylhydrazyl radical (DPPH), the reduction of ferric ion and the total polyphenol content. In addition, the activity on the plasma membrane redox system (PMRS) was evaluated in each extract. The protection against oxidative stress in erythrocytes was evaluated by determining the content of reduced glutathione (GSH) and malondialdehyde (MDA). Results. Alkaloids, flavonoids, phenolic compounds, sesquiterpene lactones and sugars were identified in all the extracts. The total polyphenols content showed a correlation with the reduction of ferric ion (r=0.885) and with DPPH radicals elimination (r = -0.899), where the one with the highest antioxidant capacity was SeR50. Thus, the SeR50 (all concentrations) and SeR70 (100 µg/mL concentration) significantly increased the PMRS activity compared to the control group. After inducing oxidative stress in erythrocytes, all the extracts maintained the GSH level and inhibited MDA formation significantly compared to the H2O2 group. Conclusion. The antioxidant capacity of hydroalcoholic extracts (96°, 70°, 50°) and aqueous infusion of Senecio rhizomatus Rusby is related to the content of polyphenols. They increase the plasma membrane redox system activity in rat erythrocytes and protect them from oxidative stress induced with H2O2, showing an increase in the concentration of reduced glutathione and a decrease in malondialdehyde.