Objective This paper aims to explore the function of Microfiber associated protein 2 (MFAP2) in thyroid cancer and its molecular mechanism of affecting angiogenesis. Methods Bioinformatics analysis was performed on the expression and enrichment pathway of target genes in thyroid cancer tissues, and the potential upstream transcription factors of target genes were predicted and their expression, correlation with target genes and binding sites were analyzed. The binding relationship between genes was verified by dual-luciferase reporter assay and Chromatin immunoprecipitation (ChIP) assay. The expression level of target gene was detected by Real time fluorescence quantitative PCR (qRT-PCR), and the expression level of signal pathway and angiogenesis related protein was detected by western blot. Cell counts kit 8 (CCK-8) assay and angiogenesis experiment were conducted to detect cell viability and angiogenesis ability. Results Bioinformatics analysis confirmed that MFAP2 was highly expressed in thyroid cancer and enriched in Notch signal pathway. Runt related transcription factor 1 (RUNX1) was positively correlated with MFAP2 expression, and RUNX1 had a binding site at 2000bp upstream of MFAP2. The qRT-PCR experiment confirmed that RUNX1 and MFAP2 were highly expressed in thyroid cancer cells (P＜0.05). The dual-luciferase assay and ChIP assay confirmed that there was a binding relationship between RUNX1 and MFAP2. CCK-8 assay and angiogenesis experiment identified that MFAP2 promoted the activity of thyroid cancer cells and tumor angiogenesis by activating Notch signaling pathway. The rescue assay confirmed that RUNX1/MFAP2 axis promoted angiogenesis of thyroid cancer through Notch signaling pathway.Conclusion In this study, we validats the carcinogenic mechanism of RUNX1/MFAP2/Node signaling network in the progression of thyroid cancer. The results suggests that the development of drug that inhibits this regulatory network may be a new approach for the treatment of thyroid cancer