In the present contribution a versatile and sustainable strategy for the formulation of a drug delivery system for the controlled release of antibiotics for topical administration was developed. Silver sulfadiazine (AgSD), an antimicrobial agent for preventing infections on burn wounds, was selected as model drug. The drug delivery system was formulated by an effective one-pot sol–gel approach by using chitosan and silica alkoxides as organic and inorganic precursor, respectively, in order to obtain a hybrid material. Different silica alkoxides, characterized by different functionalities of the organic chain, and a series of synthetic parameters (water/precursor ratio, excipients, and drug amount) were evaluated. The composition of the hybrid gel was selected to achieve the optimal synergy between the physico-chemical features and the gel texture taking into great account the final application, i.e., a topical administration. Drug delivery tests were performed in vitro with a Franz vertical diffusion cell. The new drug delivery system reaches the therapeutic concentration in the same time of a commercial sample and allows the complete release of even 2.5 wt% AgSD. The drug delivery is totally controlled and gradual over 48 h and the formulated is stable in time. Such innovative organic–inorganic hybrid material is therefore an efficient drug delivery system for acute skin infections treatment by controlled delivery.