BACKGROUND Thyroid cancer (TC) is one of the most prevalent endocrine malignancies and there may be many unclarified molecular events and gene types involved in TC. The objective of this study was to assess the clinical implications and potential mechanisms of serum response factor (SRF) in TC. MATERIAL AND METHODS RNA-sequencing and gene chip data with TC expression were collected from The Cancer Genome Atlas/Genotype-Tissue Expression, Gene Expression Omnibus, ArrayExpress, Sequence Read Archive, and Oncomine. SRF expression of all TC and adjacent non-cancerous tissue were calculated using the t test, STATA, and Meta-DiSc. The related pathways of the potential SRF target genes and target miRNAs were explored. Dual-luciferase reporter assay was performed to validate the association between SRF and its putative miRNA. RESULTS One RNA-sequencing and 15 gene chips were collected, and the pooled standardized mean difference of SRF was -1.00. Furthermore, the area under the curve of sROC of SRF in TC was 0.8251, indicating a dramatic decreased expression of SRF in TC tissues based on 1118 cases. The intersection of differentially expressed genes in TC, SRF co-expressed genes, and SRF potential target genes achieved from Cistrome Cancer led to 169 overlapped genes. miR-330-5p was predicted to target SRF, which was further confirmed by dual-luciferase reporter assay. CONCLUSIONS The reduction of SRF appears to play a crucial role in the origin of TC. These properties are accomplished by the target genes of SRF, as a transcription factor, or by the axes with the associated miRNAs.