In this study, we propose an organic solvent-free, one-step mechano-chemistry approach to engineer water-dispersible Graphene Oxide/Superparamagnetic iron oxide (GO/SPIOs) hybrids, for biomedical applications. Although mechano-chemistry has been proposed in the graphene field for applications such as drug loading, exfoliation or polymer-composite formation, this is the first study to report mechano-chemistry for preparation of GO/SPIOs hybrids. The statistical design of experiment (DoE) was employed to control the process parameters. DoE has been used to control formulation processes of other types of nano-materials. The implementation of DoE for controlling the formulation processes of graphene-based nanomaterials is, however, novel. DoE approach could be of advantage as one can tailor GO-based hybrids of predicted yields and compo-sitions. Hybrids were characterized by TEM, AFM, FT-IR, Raman spectroscopy and TGA, The dose-response magnetic resonance (MR) properties were confirmed by MR imaging of phantoms. The biocompatibility of the hybrids with A549 and J774 cell lines was confirmed by the modified LDH assay.