Fullerene is a cosmic material with a buckyball-like structure comprising 60 carbon atoms. It has attracted significant interest because of its outstanding antioxidant, antiviral, and antibacterial properties. Natural fullerene (NC60) in shungite meets the demand of biomedical fields to scavenge reactive oxygen species in many diseases. However, its hydrophobicity and poor solubility in water hinder its use as an antioxidant. In this study, highly water-dispersed and stable Pluronic-coated natural fullerene nanoaggregates (NC60/Plu) were prepared from various Pluronic polymers. The water dispersity and stability of NC60 were compared and optimized based on the characteristics of Pluronic polymers including F68, F127, L35, P123, and L81. In particular, NC60 coated with Pluronic F127 at a weight ratio of 1 to 5 showed excellent antioxidant effects both in situ and in vitro. This suggests that the high solubilization of NC60 in Pluronic polymers increases its chance of interacting with reactive oxygen radicals and improves radical scavenging activity. Thus, the optimized NC60/PF127 may be a novel biocompatible antioxidant for treating various diseases associated with oxidative stress.