Background: Interest in advanced wound dressings for clinical applications is increasing, with biopolymer-based formulations emerging as an effective strategy for wound management. Objectives: This study aimed to develop and characterize sponge-like biopolymeric matrices for the topical delivery of indomethacin as a model anti-inflammatory drug. Methods: Matrices were prepared by combining collagen and methylcellulose (MC) gels in varying ratios, followed by lyophilization. Physicochemical characterization included FT-IR, SEM, contact angle, and water absorption analysis. Biological evaluation involved enzymatic degradation, while biopharmaceutical and pharmacological assessments included in vitro drug release and in vivo testing in Wistar rats with experimentally induced burns. Results: FT-IR analysis confirmed that collagen’s triple-helical structure was preserved in the presence of MC and indomethacin for the samples with maximum 25% methylcellulose. SEM analysis revealed a microporous network with integrated cellulose fibers, where pore size decreased with higher MC content. Compressive strength measurements demonstrated enhanced mechanical resistance with increasing MC content, indicating improved structural stability of the matrices. Moreover, increased MC content led to higher contact angle values but maintained hydrophilicity, while formulations with up to 25% MC exhibited good absorption capacity and structural integrity. Enzymatic degradation studies confirmed that matrices with at least 75% collagen content maintained their structural integrity over time, favoring prolonged application and sustained drug delivery. In vitro drug release followed a biphasic profile, supporting rapid initial anti-inflammatory action followed by gradual release of the drug. In vivo animal studies demonstrated accelerated wound healing in treated rats for all tested matrices. Conclusions: Overall, the developed indomethacin-loaded biopolymeric matrices showed promising structural, functional, and therapeutic properties for effective wound treatment.