We aimed to investigate the role of F-Box protein 4 (FBXO4) in the progression of papillary thyroid cancer (PTC) and to reveal the underlying signaling pathways responsible for FBXO4 action in PTC. FBXO4 expression was evaluated in tissues from PTC patients as well as in cell lines. Overexpression of FBXO4 was re-introduced into PTC cell line B-CPAP, followed by analysis of cell migration, invasion, apoptosis and epithelial-mesenchymal transition (EMT) marker profile. An in vivo xenograft tumor mouse model was employed to address the role of FBXO4 in tumorigenesis as well. Endogenous FBXO4 was downregulated in PTC patient tissues and cell lines. Upon re-introducing its expression, FBXO4 suppressed migration and invasion and induced apoptosis of PTC cells, as well as inhibited EMT. Using a xenograft tumor mouse model, the pro-apoptotic and anti-EMT functions of FBXO4 are also validated in vivo, resulting in considerably slowed tumor growth rate of inoculated FBXO4-expressing PTC cells. Our results therefore propose the potential therapeutic value of FBXO4 in targeted treatments against PTC. Copyright © 2020 Elsevier Inc. All rights reserved.