Multifunctional Fe₃O₄ nanoparticles (NPs)/poly(N-isopropylacrylamide-co-methacrylic acid) hybrid nanospheres, i.e. Fe₃O₄/p(NIPAM-co-MAA), were synthesized via a temperature-regulated one-pot copolymerization of NIPAM and MAA in the presence of Fe₃O₄ NPs. The copolymerization includes two steps. Firstly, NIPAM monomers were initiated to fabricate PNIPAM networks with Fe₃O₄ NPs distributed throughout below the lower critical solution temperature (LCST) of PNIPAM. Secondly, PNIPAM reacted with MAA to form p(NIPAM-co-MAA) copolymers above the LCST. Meanwhile, PNIPAM networks collapsed to form nanospheres, resulting in Fe₃O₄ NPs entrapped into nanospheres. The prepared nanospheres showed outstanding temperature, pH and magnetic field sensitivities, and swelling/collapsing/flocculation properties in NaCl solutions. The nanospheres have a critical flocculation concentration of 1.0 M at room temperature. Both the volume phase transition temperature and critical flocculation temperature moved toward a lower temperature with the NaCl concentration increasing. As the increase of temperature, the required time of flocculation balance decreases, and the flocculation is relatively weak and reversible. These properties of nanospheres indicate a promising application of multi-responsive nanomaterials, especially serving as smart drug carriers, and provide a guide for preparing multifunctional inorganic/organic core/shell composites.