Polymer-based “non-stick” coatings are promising as the next generation of effective, environmentally friendly marine antifouling systems that minimize non-specific adsorption of extracellular polymeric substances (EPS). However, design and development of such systems are impeded by the poor knowledge of polymer-mediated interactions of biomacromolecules with the protected substrate. In this work, a polymer density functional theory (DFT) is used to predict the potential of mean force between spherical biomacromolecules and amphiphilic copolymer brushes within a coarse-grained model that captures essential non-specific interactions such as the molecular excluded volume effects and the hydrophobic energies. The relevance of theoretical results for practical control of the EPS adsorption is discussed in terms of the efficiency of different brush configurations to prevent biofouling. It is shown that the most effective antifouling surface may be accomplished by a good balance of the polymer chain length and the grafting density.Graphical abstract.Highlights► Colloidal forces due to amphiphilic copolymer brushes are predicted by DFT. ► The coarse-grained model captures essential nonspecific interactions. ► The theoretical results are relevant to practical control of EPS adsorption. ► Also discussed is the efficiency of different brush configurations to prevent biofouling.