This study aimed to investigate the mechanism and role of MFAP5 in papillary thyroid carcinoma (PTC), laying the foundation for future clinical treatment of PTC. Using WB and RT-qPCR to determine MFAP5 expression in PTC tissues and paracancerous tissues, as well as human normal thyroid cell lines and human PTC cell lines. Viral infection of PTC cells by overexpressing MFAP5 and knocking down EFEMP2. CCK8 and a colony formation assay were used to assess PTC cell proliferation. Kits detect glucose uptake, lactate production, and WB analyses of GLUT1, HK-II, and LDHA expression to evaluate aerobic glycolysis. Nude mice were used as xenograft models for tumor growth assessment. MFAP5. WB detects the expression of EFEMP2, Myc, cyclin D1 and β-catenin. MFAP5 expression is significantly reduced in PTC tissues and cells. MFAP5 overexpression inhibits PTC cell proliferation and aerobic glycolysis. MFAP5 overexpression activates EFEMP2 and suppresses the Wnt/β-catenin pathway. Knockdown of EFEMP2 reverses PTC cell proliferation and aerobic glycolysis. Tumor growth can be inhibited in vivo by MFAP5 overexpression, which regulates the EFEMP2/Wnt/β-catenin pathway. Overexpression of MFAP5 inhibits PTC progression and aerobic glycolysis by regulating the EFEMP2/Wnt/β-catenin pathway.