Hydrolytically labile poly(ethylene glycol)-based hydrogels are fabricated via a Michael-type addition reaction between unsaturated acrylate moieties and nucleophilic thiols. Although these gels offer the advantage of selective, in situ polymerization and potential as biocompatible matrixes for cell and protein encapsulation, a thorough understanding of the complex structure-property relationships that control the macroscopic behaviors of these cross-linked networks before and during hydrolytic degradation does not exist. Therefore, in this work, a novel theoretical model is presented to describe the formation and hydrolytic degradation of the step-polymerized gels. The model accounts for variations in hydrolysis kinetics as well as structural effects such as precursor functionality and the presence of primary cycles or other structural nonidealities that lower the cross-linking efficiency of the networks. Comparison of model predictions and experimental data validate this methodology for optimizing biomaterial design and reveal that structural nonidealities play a key role in determining the degradation behavior of real cross-linked systems. Decreasing precursor concentration and functionality during network formation generate high concentrations of network nonidealities that ultimately lead to higher initial swelling ratios and faster apparent rates of degradation.