Dual-stage release, consisting of a first fast release for eliminating the uncomfortable symptoms and a later sustained release for a long time period for reducing the administration times, is highly welcomed by the patients. In the present investigation, a new type of core-shell Electrosprayed Nanoparticles (ENPs) were developed for providing a dual-stage controlled release profile of Ketoprofen (KET). A coaxial electrospraying process was explored to prepare the core–shell particles in a directly and straightforward manner. The resultant ENPs were tested in terms of morphology and inner structure, physical state and compatibility between KET and the core matrix of ethyl cellulose, between KET and the shell matrix of polyvinyl pyrrolidone, and the dual-stage controlled release performances. The results from scanning electron microscopy and transmission electron microscope observations demonstrated that the core–shell polymeric nanohybrids had a round morphology with an average diameter of 570 ± 120 nm, and a clear core–shell structure with an estimated shell thickness of 70 nm. KET presented in the ENPs in an amorphous state thanks to the fine compatibility of the hybrid components, as verified by X-ray diffraction and fourier transform infrared spectroscopy (FTIR) tests. In vitro dissolution tests exhibited that the ENPs were able to provide a designed dual-stage controlled release profile with an amount of 45.1 ± 4.5% for the first stage.