Interest in novel delivery systems that improve the cytoprotective and antioxidant effects of natural drugs has been explored recently due to the increase in the incidence of chronic diseases in which oxidation mechanisms are involved. Curcumin is a phenolic compound recently shown to be clinically significant due to its anti-inflammatory, anticancer, and antioxidant properties. However, this molecule possesses a low bioavailability and a high degradation rate in the presence of light. Therefore, we prepared nanoparticles of poly-ε-caprolactone and Pluronic^® F-68 as a stabilizer and loaded these with curcumin (Cur–PCL nanoparticles) for antioxidant and cytoprotective applications. The nanoparticles did not induce cell death, but they did reduce cell proliferation without affecting cell migration and cell adhesion. Interestingly, Cur–PCL and poly-ε-caprolactone nanoparticles reduced the oxidative stress induced by hydrogen peroxide and presented a cytoprotective effect. Remarkably, poly-ε-caprolactone nanoparticles showed a decrement of 30% in reactive oxygen species presence compared to the positive control. The decrease of reactive oxygen species derived from the administration of poly-ε-caprolactone nanoparticles could be attributed to the presence of Pluronic^® F-68. Taken together, these data indicated that these nanoparticles might have a clinical application in disorders related to reactive oxygen species formation.