Topical semisolid formulations based on biopolymers and plant-derived components have attracted increasing attention for wound healing applications. However, their physicochemical stability and biological performance are strongly influenced by formulation composition and structural organization, which necessitates further systematic investigation. The aim of this study was to develop and optimize oil-in-water cream formulations based on biopolymer systems containing chitosan, xanthan gum, and plant extracts of Hypericum perforatum and Calendula officinalis. The formulations were prepared using a conventional emulsification method and evaluated in terms of pH, viscosity, rheological behavior, microbiological purity, and antimicrobial activity. Initial systems exhibited low viscosity and insufficient structural stability, which were improved by the incorporation of xanthan gum as a stabilizer. The optimized formulations demonstrated non-Newtonian shear-thinning behavior and pH values of 6.35 ± 0.08, indicating suitability for topical application. Formulations containing plant extracts did not exhibit antimicrobial activity against Staphylococcus aureus ATCC 6538 and Pseudomonas aeruginosa ATCC 9027. In contrast, the formulation containing naringin demonstrated selective bactericidal activity against Staphylococcus aureus up to a dilution of 1:16, with no effect observed against Pseudomonas aeruginosa. Overall, the developed systems showed appropriate physicochemical and rheological properties for dermal application. The study demonstrates that physicochemical optimization does not necessarily correlate with antimicrobial performance, highlighting the importance of formulation composition.