To elucidate the complex molecular mechanisms of anaplastic thyroid carcinoma (ATC), the mRNA and miRNA expression profiles of ATC were systematically explored. A total of 55 common differentially expressed genes (DEGs) were obtained from two mRNA expression datasets including 23 ATC samples and 24 paired normal samples. Gene expression levels of three randomly selected DEGs, VCAN, COL5A1 and KCNJ16, were examined using RT-PCR in 10 ATC samples. Notably, the ATC and normal samples were clearly classified into two groups based on their common DEGs. Moreover 23 common DEGs, such as TG, NKX2-1, KCNJ16 and CTHRC1, were predicted to be the potential targets of 17 identified miRNAs in ATC. Meanwhile, several miRNA target genes were associated with biological processes related to tumor progression such as angiogenesis, cell migration or growth and potassium channel regulation. In summary, the poor prognosis of ATC is possibly caused via complex biological processes. Firstly, angiogenesis was activated by the high expression of CTHRC1, VCAN and POSTN, providing necessary nutrition for tumor cells. Then tumor distant metastasis was induced via stimulation of cell migration and cell growth or regulation of cell-cell interaction. Moreover, intracellular potassium concentration changes promoted ATC progression indirectly. Hence, identification of these critical DEGs was valuable in understanding the molecular mechanisms of ATC.