Asymmetric sponge dressings with a hydrophobic surface and a hydrophilic inner layer can prevent bacterial infiltration and ensure efficient absorption of wound exudate. In this work, ε-polylysine/aliphatic polyurethane sponge (EPU) was prepared by prepolymer foaming process, and oxidized hyaluronic acid (OHA) was cross-linked with ε-polylysine (EPL) in EPU through schiff-base reaction to obtain EHPU. Octaisobutyl polyhedral oligomeric silsesquioxane (Oi-POSS) was uniformly sprayed onto the surface of EHPU as the hydrophobic layer, resulting in asymmetric sponge dressings denoted as P-EHPU. These dressings demonstrate capabilities in resisting staining and bacterial invasion, with internal EPL effectively inhibiting bacterial proliferation on the wound surface. The introduction of OHA and EPL leads to a denser and more complete pore structure of the sponge, endowing it with good compression, tensile strength, and hemostatic performance. Wound healing studies indicate that P-EHPU effectively prevents external bacterial infiltration and promotes wound healing.