The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p5353,54 TAD2 mutant behaves as a “super-tumor suppressor,” with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression. Display omitted •The p5353,54 TAD2 mutant is a super-tumor suppressor in pancreatic cancer•p5353,54 hyperactivates Ptpn14, a p53 target gene involved in tumor suppression•p53 negatively regulates Yap through Ptpn14 activation•p53-Ptpn14-Yap is a key tumor suppressive axis in mice and humans Mello et al. find that a p53 mutant harboring mutations in the second transcriptional activation domain has enhanced tumor suppression capacities due to hyperactivation of the p53 target gene Ptpn14. Ptpn14 suppresses Yap activity and is required for p53 tumor suppressor activity in pancreatic cancer.