Phytoecdysteroids exert significant anti-inflammatory effects, which makes them valuable ingredients in pharmaceutical and cosmetic products. However, data on their use in cosmetics are limited. Here, a new formulation with the extract of the Serratula coronata herb containing phytoecdysteroids was developed. The aim of this study was to perform physicochemical characteristics and evaluate the safety of the creams with S. coronata. Chromatography was used to detect the dominant phytoecdysteroids in the extract. The chemical and physical description of the creams was performed using the following parameters: viscosity, pH, and stability. The microbiological purity (pharmacopoeial methods) and transdermal permeability (Raman spectroscopy) were assessed to ensure the safety of the plant extracts used in the creams. The study confirmed the presence of phytoecdysteroid fractions of the S. coronata herb in the creams (20-hydroxyecdysone, polypodine B, and ajugasterone C). The results indicated that the cosmetics containing the S. coronata extract were chemically and microbiologically stable, thereby contributing to their safety. Their effectiveness is the result of transdermal permeability of 20-hydroxyecdysone. In this study, we demonstrated the importance of the S. coronata extract as a source of bioactive phytoecdysteroids and proved that the extract’s characteristics may make it the key ingredient of safe and stable skincare products that support the treatment of various inflammatory skin diseases. These results were a continuation of those presented in our earlier publication.