Mast cells (MCs) are central to the pathophysiology of type 2 inflammatory diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). During inflammation, MCs expand within the epithelium (MCTs) and exhibit phenotypic heterogeneity compared with MCs found in subepithelium (MCTCs), however, the signaling pathways driving these phenotypes are unclear. We previously demonstrated that TGF-Î² plays a role in murine intraepithelial MC development and hypothesize that TGF-Î² has a similar effect on human MCs. To test this, we used single cell RNA-sequenced nasal polyp MCs and found that TGF-Î² stimulation of in vitro peripheral blood-derived MCs (PB-MCs) directed a transcriptional program that robustly paralleled polyp MCTs. This cassette of genes included upregulation of transcription factors (SKIL, FOXP1), downregulation of granule-associated components (NDST2, CMA1, CTSG), and differential regulation of arachidonic acid metabolite enzymes (PTGS1, HPGDS). Using flow cytometry, we confirmed that TGF-Î² stimulation derived the development of MCs that possessed significantly lower chymase and cathepsin G proteases. Further, MRGPRX2, an MCTC distinguished marker, was downregulated. Interruption in TGF-Î² signaling led to increase in chymase expression similar to the response of polyp MCTs in culture. TGF-Î² drastically influenced MC production of inflammatory mediators following IgE crosslinking, including enhanced synthesis of lipid mediator, PGD2 and CysLTs, and chemokines (IL-8 and MIP-1Î²), and selective suppression of cytokines (IL-13 and TNF-Î±). Thus, TGF-Î² was central in driving the human MCT phenotype, altering both the MC protease profile and their response to activating stimuli.