The sensing layer in electronic device, such as chemical sensor, is an important and functional component consisting of polymer, organic materials, inorganic particles, and other components. These materials are generally hierarchical and porous with a large effective specific surface area to achieve the required surface chemical reactions. Despite the great progress, the synthesis of hollow core-shell nanostructure, especially ternary transition metal with core-in-hollow-shell nanostructure, is rarely reported. Herein, a novel NiFe2O4 core-in-hollow-shell nanosphere with a porous inner and outer surface was prepared by a hydrothermal and co-precipitation method and the acetone sensing properties were reported. The NiFe2O4 sensing layer exhibited high response to 100 ppm acetone gas (10.6) and achieved a rapid response rate and recovery process (within 1 s/7 s) at 280 °C, which are superior over those for nanoparticles of NiFe2O4 and those reported for similar devices. In addition, after 20 days, the response of sensor based on NiFe2O4decreased ～4%, indicating an alluring long-term stability. This is attributed to the highly porous but robust core-shell architecture, large utilization ratio of sensing layer and excellent catalytic activity.