A two-pot method is reported for the synthesis of ferric oxide-gluconic acid/β-cyclodextrin (Fe3O4-GA@β-CD). The proposed approach is a green one as the raw material is a natural product (sucrose) and no organic solvent is involved. Meanwhile, this novel composite was demonstrated for catalytic degradation of p-nitrophenol (PNP), a prototype toxic with high toxicity and low degradability. This is realized by H2O2 activation induced by the heterogeneous Fenton-like catalysis of the as-prepared Fe3O4-GA@β-CD nano-microspheres. The results showed that the reaction rate constants of PNP degradation catalyzed by Fe3O4-GA@β-CD and Fe3O4-GA were 0.0879 and 0.0514 min−1, respectively, suggesting improved catalytic performance of Fe3O4-GA@β-CD compared with Fe3O4-GA. This can be attributed to the cavity of β-CD, which can capture and include PNP molecules. The effects of pH value, H2O2 concentration, catalyst load and hydroxyl radical quenching on the Fenton-like catalysis were explored and the optimized conditions (pH value = 2.0, H2O2 concentration = 50 mM, and catalyst load = 1.0 g/L) were determined. Additionally, Fe3O4-GA@β-CD exhibited excellent reusability (catalytic degradation rate = 95.1% after five recycling times) as it can be recycled under external magnetic field owing to its good magnetic response (up to 18.41 emu/g).