Display omitted We synthesized composite microspheres from cellulose nanocrystal (CNC), polyvinyl alcohol (PVA), and sodium alginate (SA), which were modified with polyethyleneimine (PEI) to introduce a high density of active amino sites onto the surface via the Schiff base reaction. We hypothesized that these (SA/CNC/PVA)@PEI microspheres would have a high adsorption capacity for aqueous diclofenac sodium (DS). The PEI-modified composite microspheres were characterized and assessed and optimized for aqueous DS adsorption. In addition, the morphology and synthesis mechanism of the adsorbent were studied. The adsorption process showed a good fit with the pseudo-second-order kinetic model (i.e., the process is driven by a chemical adsorption mechanism) and Langmuir adsorption isotherm model (i.e., adsorption follows a single-layer process). Under the optimum experimental conditions (pH: 4.5, adsorption time: 50 min, temperature: 303 K), the maximum adsorption capacity was 418.4104 mg/g, which was relatively high compared to other reported adsorbents. Importantly, after five adsorption–desorption cycles, (SA/CNC/PVA)@PEI showed only a slight loss in adsorption capacity. Compared with other reported adsorbents, the core–shell composite has a good DS adsorptive capacity and high recyclability.