Rational design and modification of the all-carbon fullerene cages to meliorate their nature of hydrophobicity is critical for biomedical applications. The outstanding electron affinity of fullerenes enables them to effectively eliminate reactive oxygen species (ROS), the excess of which may lead to health hazards or biological dysfunction. Herein reported is a facile, mild, and green approach to synthesizing the favorable water-soluble C60 nanoparticles capable of ROS-scavenging by combining the mussel-inspired chemistry with the Michael addition reaction. Various characterization techniques, including Fourier-transform infrared spectroscopy (FTIR), X-ray photoelectron spectra (XPS), thermogravimetric analysis (TGA), transmission electron cryomicroscopy (Cryo-TEM), and dynamic laser scattering (DLS) were carried out to confirm the satisfactory preparation of the hybrid C60-PDA-GSH nanoparticles, which exhibited apparent scavenging capacity of DPPH and hydroxyl radicals in vitro. Additionally, the biocompatible C60-PDA-GSH nanoparticles entered into cells and displayed a universal cytoprotective effect against oxidative press induced by H2O2 in four kinds of human cells at a low concentration of 2 μg/mL. The ease and versatility of the strategy present in this work will not only trigger more fullerene-based materials by the immobilization of diverse functional molecules, but will also extend their possible applications.