Purpose: To detect low-frequency mutation in the 57 genes of small panels that are associated with developing thyroid cancer in papillary thyroid carcinoma (PTC) patients and provide patients with precise-targeted therapy. Patients and Methods: This study included 144 patients diagnosed with PTC who underwent total thyroidectomy and lymph node dissection in the central area of the neck between May 2017 and October 2018. We performed ultra-deep sequencing of 57 genes from 144 patients and detected the 57 genes mutations with bioinformatics. Results: There were 698 mutations in 45 genes from 138 PTC patients. A high frequency of mutations was detected in the RBM10 gene (44%) and TERT (43%), and some hotspot mutations, such as RBM10:p.E119D and TERT:p.P112fs, were also found. Conclusion: Ultra-deep sequencing of small gene panels can find some low-frequency mutation genes, which can provide targeted therapy for patients.