Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. Recent studies have revealed that interactions between pathogenic microorganisms, which have a tendency to parasitize the skin of AD patients, play a significant role in the progression of the disease. Furthermore, specific species of commensal bacteria in the human intestinal tract can have a profound impact on the immune system by promoting inflammation and pruritogenesis in AD, while also regulating adaptive immunity. Natural products (NPs) have emerged as promising agents for the treatment of various diseases. Consequently, there is growing interest in utilizing natural products as a novel therapeutic approach for managing AD, with a focus on modulating both skin and gut microbiota. In this review, we discuss the mechanisms and interplay between the skin and gut microbiota in relation to AD. Additionally, we provide a comprehensive overview of recent clinical and fundamental research on NPs targeting the skin and gut microbiota for AD treatment. We anticipate that our work will contribute to the future development of NPs and facilitate research on microbial mechanisms, based on the efficacy of NPs in treating AD.