The drug release behavior of pH-sensitive starch-based hydrogels was systematically studied. Hydrogels were synthesized by copolymerization of acrylic acid (AA) and other acrylate comonomers onto the starch backbone. The hydrophilic agents 2-hydroxy ethyl methacrylate (HEMA), and acrylamide (AAm), as well as the hydrophobic butyl-methacrylate (BMA), were utilized as comonomers. Methylene-bisacrylamide (MBA) was employed as a crosslinking agent. The synthesized hydrogels were loaded with caffeine as a model drug. The effects of the hydrophobic/hydrophilic character of the comonomers and chemical crosslinking on the swelling capacity and the release rate of caffeine were investigated. The use of the crosslinking agent and hydrophobic monomers decreased the swelling capacity of the hydrogels. The release rate of caffeine increased with the presence of a hydrophobic monomer. The fastest release was obtained with the AA/BMA/AAm formulation, and the slowest release was observed with the AA/HEMA/AAm formulation. The transport mechanism was controlled by Fickian diffusion in formulations containing AAm, and controlled by the polymer-relaxation mechanism in formulations containing MBA. Overall, our results showed that the swelling and drug delivery behavior can be tuned by varying the chemical composition of the copolymer formulations. These starch-based hydrogels can be useful as drug delivery devices in many biomedical applications.