The novel, highly active, acid resistance and reusable immobilized adsorbent, 2-phosphonobutane-1,2,4-tricarboxylic acid (PBTCA)-decorated chitosan-coated magnetic silica nanoparticle, has been fabricated and applied to the highly selective adsorption of uranium from a multi-ion solution. Display omitted •Novel PBTCA-decorated chitosan-coated magnetic SiO2 nanoparticles were fabricated.•A new, highly active, acid resistance, and reusable magnetic sorbent was obtained.•Coexisting ion experiments showed highly selective uranium adsorption.•CoFe2O4@SiO2@CS-PBTCA showed higher acid resistance than uncoated silica adsorbent.•Adsorbent binds to uranium mainly though carboxyl and phosphonic oxygen atoms in PBTCA. The separation and recovery of uranium resources from nuclear waste solutions is important for achieving uranium reuse and environmental protection. In this study, a novel adsorbent, 2-phosphonobutane-1,2,4-tricarboxylic acid (PBTCA)-decorated chitosan-coated magnetic silica nanoparticles, was fabricated and applied to the highly selective adsorption of uranium from aqueous solution. Selective sorption in a multi-ion solution (pH 4.0) containing 14 coexisting cations resulted in CoFe2O4@SiO2@CS-PBTCA showing an excellent uranium adsorption capacity of up to 83.16 mg g−1, which was much higher than that of ungrafted CoFe2O4@SiO2@CS (29.99 mg g−1). The adsorbent also exhibited higher acid resistance than uncoated silica adsorbent under pH 1.0 conditions, with CoFe2O4@SiO2@CS-PBTCA showing barely any iron and cobalt leaching, while CoFe2O4@CS-PBTCA showed iron and cobalt leaching amounts of 2.97 and 0.93 mg L−1, respectively. The desorption experiment used 0.2 M PBTCA (pH 1.0) as eluent, with the results showing that uranium ions were readily and rapidly desorbed. Furthermore, CoFe2O4@SiO2@CS-PBTCA maintained outstanding stability and adsorption performance after five reuse cycles. The mechanism for U(VI) removal was investigated by X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy, with the results suggesting that the adsorbent binds to uranium mainly though oxygen atoms of carboxyl groups and phosphonic groups in PBTCA. This strategy shows strong potential for developing a variety of novel, highly active, acid resistance, and reusable immobilized functional magnetic materials for effective separation of uranium from a multi-ion solution.