Furin belongs to the pro‐protein convertases (PCs) family and its aberrant expression has been documented in various types of cancers; however, its role in thyroid cancer remains unclear. We investigated the expression of furin in a large cohort of Middle Eastern papillary thyroid carcinoma (PTC) patient samples and explored its functional role and mechanism in PTC cell linesin vitroandin vivo. Furin overexpression was observed in 44.6% of all PTC cases and was significantly associated with aggressive clinicopathological parameters and poor outcomes. We show that the knockdown ofFURINsuppresses tumor growth, proliferation, migration, invasion, spheroid growth, and progression of epithelial‐to‐mesenchymal transition (EMT) in B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) mutant cells, whereas its overexpression inBRAFwild‐type PTC cell lines reversed the effect.FURINknockdown in theBRAFmutant cell line led to reduced tumor growth and increased apoptosis. Mechanistically,FURINknockdown led to MEK/ERK pathway suppression inBRAFmutant cells, although inhibition of MEK did not affect furin expression, which suggests that furin acts through the MEK/ERK pathway. Furthermore, our study revealed the synergistic antitumor effect of furin depletion and anti‐MEK inhibitor treatment. Overall, these results indicate that furin is an important prognostic marker in Middle Eastern PTC and that it plays a crucial role inBRAF‐associated MAP/ERK pathway activation and tumorigenesis. Furin inhibition could be a potential therapeutic target for aggressive PTC.