We present an efficient approach to develop cellulose nanocrystal (CNC) hybrids with magnetically responsive Fe3O4 nanoparticles that were synthesized using the (Fe3+/Fe2+) coprecipitation. After 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO)-catalyzed oxidation of CNC, carbodiimide (EDC/NHS) was used for coupling amine-containing iron oxide nanoparticles that were achieved by dopamine ligand exchange (NH2-Fe3O4 NPs). The as-prepared hybrids (Fe3O4@CNC) were further complexed with Cu(II) ions to produce specific protein binding sites. The performance of magnetically responsive Cu-Fe3O4@CNC hybrids was assessed by selectively separating lysozyme from aqueous media. The hybrid system displayed a remarkable binding capacity with lysozyme of 860.6 ± 14.6 mg/g while near full protein recovery (∼98%) was achieved by simple elution. Moreover, the regeneration of Fe3O4@CNC hybrids and efficient reutilization for protein separation was demonstrated. Finally, lysozyme separation from matrices containing egg white was achieved, thus revealing the specificity and potential of the presented method.