Background The incidence of papillary thyroid cancer (PTC) has increased rapidly in recent decades, and tumor progression events are common in PTC. The purpose of our study is to identify the differentially expressed genes (DEGs) correlated with PTC progression and investigate the function of PDZK1IP1 (PDZK1 interacting protein 1) in PTC. Methods We first analyzed DEGs associated with PTC progression between paired PTC and normal thyroid tissues in 3 Gene Expression Omnibus data sets (GSE29265, GSE33630, and GSE60542) and The Cancer Genome Atlas (TCGA) database. Data from the TCGA database and our institution were utilized to explore the relationship between PDZK1IP1 expression and clinicopathological characteristics of PTC. The CCK8 cell proliferation assay, clone formation assay, flow cytometry assay, and the xenograft model were used to investigate the function of PDZK1IP1 in PTC. Results Thirty-nine DEGs associated with PTC progression were identified, in which only PDZK1IP1 was upregulated in PTC tissue at both messenger RNA and protein levels. In addition, we found that high expression of PDZK1IP1 in the TCGA database was associated with poor progression-free survival, extrathyroidal extension, high stage, tall cell variant, and BRAF(V600E) mutation of the PTC (P < 0.001). In our collected samples, high expression of PDZK1IP1 was only related to lymph node metastasis (P < 0.05). Overexpression of PDZK1IP1 significantly promoted proliferation and inhibited apoptosis of PTC cells. Knockdown of PDZK1IP1 significantly inhibited proliferation, promoted apoptosis, and prevented xenograft formation of PTC cells. Conclusion PDZK1IP1 is an oncogene for tumorigenesis and development of PTC and might be a potential therapeutic target.