Objective. Inflammatory skin disorders are becoming major issues threatening public health with increasing prevalence. This study was to evaluate the anti-inflammatory, antioxidant, and antisenescent activities of traditional folk medicinal plant, Physalis alkekengi L. extracts to alleviate skin inflammation and its possible mechanisms. Methods. Lipopolysaccharides (LPS)-treated murine macrophages RAW264.7 and human skin keratinocytes HaCaT were incubated with the plant extracts, respectively. The production of nitric oxide (NO) was tested by using Griess reagents. The activity of nitric oxide synthase (NOS) was detected through a fluorescence microplate reader. Reactive oxygen species (ROS) production and cell apoptosis were quantified by flow cytometry. The proinflammatory cytokines were measured using ELISA and qRT-PCR. Human skin fibroblasts (HFF-1) were coincubated with D-galactose (D-gal) and the plant extracts. The senescence associated-galactosidase (SA-β-gal) was stained to evaluate cellular senescence. The senescence-associated secretory phenotype (SASP), IL-1β, was measured through ELISA. The mRNA of IL-1α in SLS-stimulated and PGE2 in UV-radiated 3D skin models were detected by qRT-PCR. In vivo ROS production and neutrophil recruitment in CuSO4-treated zebrafish models were observed by fluorescence microscopy. Inflammation-related factors were measured by qRT-PCR. Results. In vitro, Physalis alkekengi L. significantly reduced NO production, NOS activity, cell apoptosis, transcription of TNF-α, IL-6, IL-1β and ROS production. These plant extracts markedly attenuated SA-β-gal and IL-1β and downregulated the production of IL-1α and PGE2. In vivo, the plant extracts dramatically dampened ROS production, the number of neutrophils, and proinflammatory cytokines. Conclusions. Cumulatively, this work systematically demonstrated the anti-inflammatory, antioxidant, and antisenescent properties of Physalis alkekengi L. and proposed the possible roles of Physalis alkekengi L. in inflammatory signaling pathways, providing an effective natural product for the treatment of inflammatory skin disorders.