Controlling the release rate of anticonvulsant drugs can have a significant effect on the efficacy of these drugs and the safety with which they can be administered to patients. This study investigated in vitro release of the anticonvulsant ethosuximide from nanocapsule-based N,O-carboxymethyl chitosan and hyaluronan-methylcellulose hydrogels using two experimental designs: a one-factor-at-a-time method and an optimization method employing a Taguchi design. Using the first method, the release rate of the drug was significantly reduced compared with other delivery systems. With the second method, when the drug was blended into a hyaluronan-methylcellulose hydrogel the release rate was similarly reduced, with full release occurring after three days. Scanning electron microscopy, Fourier-transform infrared spectroscopy, and ultraviolet-visible spectrophotometry were used to study the drug encapsulation, and two mathematical models for evaluating encapsulation efficiency were developed. The results of this study show promise for use of nanoencapsulated thermoresponsive hydrogels in clinical delivery of anticonvulsants.