Hydrogels, particularly multifunctional hydrogels, are attractive wound dressings due to their abundant exudate absorption performance, oxygen permeability, comparable moisturizing ability, and performance of locally delivering therapeutic drugs. However, it is challenging to achieve hydrogels that possess mechanical properties comparable to those of human skin and can uniformly load hydrophobic drugs as multifunctional dressings for wound management. Herein, we report a simple and rapid fabrication of hydrogels by directly inducing sericin protein gelation using acetic acid. The resulting sericin hydrogels demonstrated high transparency and excellent physicochemical and biological properties, making them promising wound dressing materials. Notably, this sericin hydrogel system could encapsulate hydrophobic drugs during gelation, thus overcoming the limitation of inadequate amounts and non-uniform loading of therapeutic drugs in hydrogels. Further, we selectively encapsulated hydrophobic ciprofloxacin (CIP) into the sericin hydrogel to obtain a multifunctional wound dressing with favorable antimicrobial activity. The obtained CIP-loaded sericin hydrogel exhibited antibacterial activity against both Gram-positive bacteria (S. aureus) and Gram-negative bacteria (P. aeruginosa) in vitro. The in vivo studies demonstrated that the CIP-loaded sericin hydrogel effectively eliminated bacteria in wounds and significantly accelerated wound healing. Taken together, this sericin hydrogel system is potentially a promising dressing material for wound management.