Paired-related homeobox transcription factor 2 (PRRX2) belongs to the subfamily of homeobox genes and has been implicated as an oncogene in numerous cancer types, yet its role in pancreatic cancer requires further investigation. The aim of this study was to investigate the involvement of PRRX2 in pancreatic cancer progression. Bioinformatics analysis revealed that PRRX2, a transcription factor associated with senescence, was significantly upregulated in pancreatic cancer, and its heightened expression correlated with poor prognosis. Knockdown of PRRX2 led to an increased proportion of senescent cells and diminished proliferative, invasive, and metastatic capabilities, whereas PRRX2 overexpression yielded opposite effects. Subsequent experiments demonstrated that PRRX2 directly enhanced the transcription of GLI2, subsequently activating the hedgehog pathway, thereby inhibiting tumor senescence and promoting cell proliferation, invasion, and metastasis. Hedgehog pathway inhibitors or silencing of GLI2 partially reversed these effects. Additional replication experiments revealed that senescence inducers could partially counteract the impact of PRRX2 on pancreatic cancer. In conclusion, PRRX2 may serve as a potential therapeutic target for pancreatic cancer treatment.