Hydrogels are promising materials for biomedical applications, where timely degradation is often preferred. In the conventional design, however, the cleavage of polymer networks essentially causes considerable morphological changes (i.e., degradation-induced swelling), triggering various medical complications. Herein, we report a rational strategy to suppress the degradation-induced swelling based on the synthetic control of the polymer-solvent interaction parameter (χ) of constituent polymer networks. The resultant hydrogels with an optimal χ parameter (χ37 °C ≈0.53; non-osmostic hydrogels) displayed the capability to retain their original shape and degrade without generating significant swelling pressure under physiological conditions (Π37 °C <1 kPa). This concept of the safely degradable non-osmotic hydrogel is theoretically universal, and can be exploited for other types of synthetic hydrogels in various settings.