In recent years, stimuli-responsive degradation has emerged as a desirable design criterion for functional hydrogels to tune the release of encapsulated payload as well as ensure degradation of the gel upon completion of its function. Herein, redox-responsive hydrogels with a well-defined network structure were obtained using a highly efficient thiol-disulfide exchange reaction. In particular, gelation occurred upon combining thiol-terminated tetra-arm polyethylene glycol (PEG) polymers with linear telechelic PEG-based polymers containing pyridyl disulfide units at their chain ends. Rapid gelation proceeds with good conversions (>85%) to yield macroporous hydrogels possessing high water uptake. Furthermore, due to the presence of the disulfide linkages, the thus-obtained hydrogels can self-heal. The obtained hydrogels undergo complete degradation when exposed to environments rich in thiol-containing agents such as dithiothreitol (DTT) and L-glutathione (GSH). Also, the release profile of encapsulated protein, namely, bovine serum albumin, can be tuned by varying the molecular weight of the polymeric precursors. Additionally, it was demonstrated that complete dissolution of the hydrogel to rapidly release the encapsulated protein occurs upon treating these hydrogels with DTT. Cytotoxicity evaluation of the hydrogels and their degradation products indicated the benign nature of these hydrogels. Additionally, the cytocompatible nature of these materials was also evident from a live/dead cell viability assay. One can envision that the facile fabrication and their ability to degrade on-demand and release their payload will make these benign polymeric scaffolds attractive for various biomedical applications.