This study describes the synthesis of polymeric microspheres by reversed-phase graft polymerization of native gelatin (GL) and sodium methacrylate, which are useful as stimuli-responsive drug delivery devices. By means of varying the GL/functional monomer ratios (2.0–0.5 w/w), formulations with different crosslinking degrees, dimensional distributions, and water affinities were synthesized. The hydrogels showed spherical shape, porous surface, and high water affinity at neutral pH value with respect to the acidic conditions, with the ratio between the swellings, at pH 7.0 and 1.0, being in the range 3.7–5.1. In vitro release studies, using diclofenac sodium salt, in neutral and acidic media, simulating biological fluids, were performed. For all formulations, low amounts of drug (Mt/M0 percent <20.0%) are released in acidic medium. When the pH is 7.0, the swelling of the network increases, and the drug molecules diffuse through the polymeric structure. By means of semi-empirical equations, the release mechanism was studied, and the diffusional contribute was evaluated.