Rosacea is a chronic inflammatory skin disease and its pathogenesis remains unclear. Key genes were screened in the GSE155141 and GSE65914 datasets through a bioinformatics approach. To establish a rosacea-like mouse model with periostin (POSTN) knockdown, mice were subcutaneously injected with lentivirus-packaged Lv-shPOSTN, followed by LL37 treatment on the dorsal skin. Skin tissues were collected for the assessment of skin lesion area, skin thickness, redness score, as well as for hematoxylin and eosin (HE) staining, toluidine blue staining, and immunofluorescence staining. The inflammatory factors and chemokine levels were determined by enzyme-linked immunosorbent assay. Wound healing and Transwell assays were performed to assess cell migration and invasion. Phosphorylation levels of JAK2, STAT3, IKKβ, and p65 were evaluated via western blotting. Hub genes, including COL1A2, POSTN, LOX, BGN, COL3A1, DCN, and COL1A1 were screened. POSTN was highly expressed in rosacea and POSTN silencing ameliorated pathological changes and suppressed inflammation, immune infiltration, and angiogenesis. The levels of inflammatory factors (TNF-α, IL-1β, and IL-6) and chemokines (CCL2, CXCL10, and CXCL2), as well as the KLK5, CAMP, TLR2, and VEGF expression levels were reduced after POSTN knockdown. POSTN silencing inhibited migration and invasion of LL37-induced human umbilical vein endothelial cells (HUVEC). Importantly, POSTN silencing suppressed the JAK2/STAT3 and NF-κB pathways both in vivo and in vitro. POSTN knockdown suppresses inflammation and angiogenesis in rosacea possibly by obstructing the JAK2/STAT3 and NF-κB pathways, which offers a potential therapeutic strategy for rosacea.