An important aspect to be considered in the healing of acute or chronic cutaneous wounds is the associated potential infection management. Collagen, the most abundant protein of the extracellular matrix, with proven properties in wounds healing and tissues regeneration, is one of the most widely used biopolymers as carrier matrix for controlled drug delivery systems. For this reason, the purpose of the current paper is the development of some minocycline-loaded collagen topical sponges uncross-linked and cross-linked with glutaraldehyde, obtained by lyophilization of appropriate hydrogels prepared according to the 3-factor, 3-level face-centered central composite design. The determination of drug delivery from the sponges was performed by assessment of some physicochemical parameters involved in this complex process: sponges surface wettability, swelling ratio and the percentage of minocycline released from the sponges. The application of the response surface methodology allowed the setting of the formulation parameters optimum ranges, which ensure an adequate minocycline release to the application site. The design robustness was checked using the signal-to-noise ratio performance indicator. The optimum collagen-minocycline sponges determined based on the statistical screening technique could be suitable for topical drug delivery in infected wounds healing with moderate to high exudate.