Nonradical activation of peroxydisulfate (PDS) is promising for wastewater decontamination but suffers from insufficient decomposition efficiency toward organics. Herein, NiO nanospheres with hollow multi-shelled structure (HoMS) and tunable shell numbers are designed as a nanoreactor of PDS activation to enhance the decomposition efficiency. Study on bis-phenol A (BPA) degradation reveals that 3-shelled NiO HoMS exhibits enhanced kinetic rate (0.08 min1) and mineralization degree (79.2%) compared to 2-shelled NiO HoMS (0.04 min−1, 50%) and NiO nanoparticles (0.01 min−1, 29.8%). The degradation of BPA over NiO HoMS follows electron transfer regime with oxygen vacancy (VO) acted as the active site. The hollow multi-shelled structure not only increases the accessibility of VO but also enriches local concentration of reactants in the void spaces due to the nanoconfinement effect, and thus mainly contributes to the enhanced catalytic efficiency. This work provides a distinct case for developing efficient nonradical oxidation technique for water purification.