This paper highlights the use of hydrogels in controlled drug delivery, and their application in stimuli responsive, especially electro-responsive, drug release. electro-conductive hydrogels (ECHs) displaying electro-responsive drug release were synthesized from semi-interpenetrating networks (semi-IPNs) containing a poly(ethyleneimine) (PEI) and 1-vinylimidazole (VI) polymer blend as the novel electro-active species. The semi-IPNs are systems comprised of polyacrylic acid (PAA) and poly(vinyl alcohol) (PVA). This paper attempts to investigate the various attributes of the electro-responsive ECHs, through institution of a statistical experimental design. The construction of a Box–Behnken design model was employed for the systematic optimization of the ECH composition. The design model comprised of three variables, viz. poly(ethyleneimine) volume; 1-vinylimidazole volume; and applied voltage, critical to the success of the formulation. Electro-responsive drug release was determined on formulations exposed to varying environments to ascertain the optimal environment for the said desired release. A comparison method of formulation water content and swelling through gravimetric analysis was also conducted. Matrix resilience profiles were obtained as an insight to the ability of the ECH to revert to its original structure following applied stress. Response surface and contour plots were constructed for various response variables, namely electro-responsive drug release, matrix resilience and degree of swelling. The outcomes of the study demonstrated the success of electro-responsive drug release. The findings of the study can be utilized for the development of electro-responsive delivery systems of other drugs for the safer and effective drug delivery. Volumes of poly(ethyleneimine) (>2.6 mL) and 1-vinylimidazole (>0.7 mL), resulted in ideal therapeutic electro-responsive drug release (0.8 mg) for indomethacin. Lower amounts of poly(ethyleneimine) and amounts of 1-vinylimidazole ranging from 0.2 to 0.74 mL are consistent with greater than 1.6 mg release per stimulation. Swelling of <25–45% was seen.