Pancreatic cancer (PC) is a complex and multifactorial human malignancy with a low survival rate. Tumor protein D52 (TPD52) was abnormally expressed in several cancers and participated in tumorigenesis. However, the oncogenic effect of TPD52 on PC remains unknown. In the present study, after transfecting AsPC-1 and PANG1 cells with NC or sh-TPD52, the CCK-8 assay, I loechst staining, western blot, transwell assay, flow cytometry were used to examine the cell proliferation, migration, invasion and apoptosis. qRT-PCR results confirmed that the expression of TPD52 was significantly increased in PC cells, especially AsPC-1 and PANGI cells. The present study revealed that silencing of TPD52 significantly suppressed the proliferation, migration and invasion, but induced apoptosis of AsPC-1 and PANC-1 cells in vitro by dephosphorylating Akt at Ser473. Conversely, SC79, an Akt activator, could partially reverse the anti-metastatic effects of sh-TPD52, accompanied by the reactivating of Akt pathway. Additional in vivo studies are warranted to elucidate that knockdown of TPD52 could inhibit tumor growth in PC mice models. These findings suggested that TPD52 might be a novel therapeutic target for PC treatment.