An efficient process for the synthesis of degradable hydrogels containing octa-betaine ester polyhedral oligomeric silsesquioxane (POSS) through efficient thiolene and Menschutkin click reactions was developed. The hydrogels exhibited a yield strength of 0.36 MPa and a compressive modulus of 4.38 MPa and displayed excellent flexibility as well as torsion resistance. Antibacterial efficacy of hydrogels (and degradation products) was evaluated using Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive). Efficacy was found to increase with the concentration of cetyl chloroacetate (CCA) in the hydrogel network, reaching 93% and 99% for Escherichia coli and Staphylococcus aureus, respectively. Degradation of hydrogels was observed in weak alkali conditions (pH = 8) and at physiological conditions (pH = 7.4). The degradation time of the hydrogels could be finely tuned by variation of the CCA content in the hydrogel and environmental stimulus. The tunable degradation behavior under physiological conditions combined with high antibacterial efficacy could render the presented materials interesting for tissue engineering applications.