Promotion of wound or bone healing and reduction of inflammation are commonly known therapeutic qualities of comfrey (Symphytum officinale). Given the presence of active constituents, including allantoin and phenolics, comfrey is widely used in cosmetic and pharmaceutical industries. The aim of this study was to optimize a three-solvent system (water, ethanol, 1,3-propanediol) to maximize the extraction efficiency of allantoin, rosmarinic acid, rabdosiin, and globoidnan A in accordance with the approach of the simplex centroid mixture design. Polynomial regression models of the mixture composition showed the impact of the extracts on cytotoxicity, metalloproteinase inhibition activity, and antioxidant properties response. Additionally, the physical properties, including surface tension and contact angle of the mixture composition, were measured. Based on the maximization of the extraction efficiency of all compounds, an optimum solvent composition was determined as 30.9% of water, 39.2% of ethanol, and 29.9% of propanediol. Such a mixture allowed extraction of 93.6%, 96.8%, 77.0%, and 97.2% of the total amount of allantoin, rosmarinic acid, rabdosiin, and globoidnan A, respectively. The optimal mixture composition for extraction of the compounds was not correlated with inhibition of metalloproteinase activity and cell viability, while a strong positive relationship with antioxidant properties was observed. The optimized solvent composition ensured good extraction efficiency, and the extract had high antioxidant properties. In the near future, in vivo studies with instrumental methods should be conducted to evaluate the practical application of the extracts in the cosmetic industry.