Integumentary system is the largest essential organ of the human body, conversely, there are several diseases/disorders allied with it. Skin disorders (inflammation, infection, and cancer) globally affect all ages, sexes, people-lifestyle and drastically reduces the quality of life along with decreased life expectancy. Unfortunately, billions of dollars and valuable patients’ time are spent on its prevention, cure, and care. There are several oral, parenteral, or topical based formulations/dosage forms used for treating various skin pathologies. Due to decreased bioavailability, adverse effects, and hypersensitivity related complications, new novel skin formulations are currently being investigated. At present, various natural products are commonly utilized and high in demand due to the presence of beneficial bioactive, exhibit multipotent pharmacodynamics effects with no/minimal contraindications. Thuja occidentalis contain essential oils, coumarins, flavonoids have exhibited antioxidant, anti-inflammatory, anti-carcinogenic, antibiotic, and trophic actions which renders them a reasonable natural product to be used for preventing and treating various pathologies in humans. However, Thuja occidentalis has several concerns associated with its oral routes. Subsequently, topical routes would be more therapeutically beneficial, which lowers the risk of systemic adverse effects with reduces the chances of drug interactions. Phytosomes, are an innovative drug delivery system for the current and future global health care. In the current study, novel phytosomal formulations with the Thuja occidentalis extract were formulated and additionally evaluated for stability (based on stability and storage, drug content and entrapment, morphological studies, Scanning Electron Microscopy, particle size, solubility, spreadability studies), in vitro release (Quercetin), and in vivo skin hypersensitivity reactions. Novel phytosomal formulations of Thuja occidentalis were stable, exhibited high bioavailability, and more prominently had no in vivo allergic manifestations. Thus, valid phytosomal formulations of Thuja occidentalis can be a suitable cosmetic and pharmaceutical dosage form for preventing and therapeutically treating various skin-based diseases/disorders.