Atopic dermatitis (AD) is a common, chronic, and recurring inflammatory skin disease. Physalis alkekengi L. var. franchetii (Mast) Makino (PAF), a traditional Chinese medicine, is primarily used for the clinical treatment of AD. In this study, a 2,4-dinitrochlorobenzene-induced AD BALB/c mouse model was established, and a comprehensive pharmacological method was used to determine the pharmacological effects and molecular mechanisms of PAF in the treatment of AD. The results indicated that both PAF gel (PAFG) and PAFG+MF (mometasone furoate) attenuated the severity of AD and reduced the infiltration of eosinophils and mast cells in the skin. Serum metabolomics showed that PAFG combined with MF administration exerted a synergistic effect by remodeling metabolic disorders in mice. In addition, PAFG also alleviated the side effects of thymic atrophy and growth inhibition induced by MF. Network pharmacology predicted that the active ingredients of PAF were flavonoids and exerted therapeutic effects through anti-inflammatory effects. Finally, immunohistochemical analysis confirmed that PAFG inhibited the inflammatory response through the ERβ/HIF-1α/VEGF signaling pathway. Our results revealed that PAF can be used as a natural-source drug with good development prospects for the clinical treatment of AD.