Objectives: This study aims to evaluate the effects of topical creams containing mucopolysaccharide polysulfate (MPS) on wound healing using an experimental wound model. Materials and methods: Standard full-thickness skin defects were created in 32 Wistar rats and monitored for 14 days under four different topical treatment protocols: Control (Group 1, n = 8), Hirudoid (Group 2, n = 8), Silverdin (Group 3, n = 8), and Hirudoid + Silverdin (Group 4, n = 8). Wound closure rates were quantified through photographic analysis, while histological and immunohistochemical healing characteristics were assessed using the Structure, Presence of Cells, Organization, and Tissue Integration (SPOT) score, additional histological indices, and the transforming growth factor-beta 1 (TGF-β1) H-score. Intergroup differences were analyzed using appropriate non-parametric statistical tests. Results: On Day 3, wound closure rates were higher in the Hirudoid, Silverdin, and Hirudoid + Silverdin groups compared to the control group (p < 0.01). By Day 14, this difference sustained only in the Silverdin and Hirudoid + Silverdin groups, indicating that the early advantage observed with Hirudoid alone was not maintained over time (p < 0.01). No significant differences in the general histological parameters were observed among the groups (p > 0.05). However, the TGF-β1 H-score was lower in the Silverdin group than in the control and Hirudoid groups (p < 0.01). Conclusion: Our study results suggest that MPS may accelerate early wound closure, but does not significantly improve wound closure in later stages, and its combination with silver sulfadiazine offers no additional benefit compared to silver sulfadiazine alone.