The tumor-suppressive function of p53 is frequently disrupted by mutations in cancers. Missense mutant p53 (mutp53) protein often stabilizes and accumulates to high levels in cancers to promote tumorigenesis through the gain-of-function (GOF) mechanism. Currently, the mechanism of mutp53 accumulation and GOF is incompletely understood. Here, we identify the lipogenic enzyme FASN as an important regulator of mutp53 accumulation and GOF. FASN interacts with mutp53 to enhance mutp53 palmitoylation, which inhibits mutp53 ubiquitination to promote mutp53 accumulation and GOF. Blocking FASN genetically or by small-molecule inhibitors suppresses mutp53 palmitoylation to inhibit mutp53 accumulation, which in turn inhibits the growth of mutp53 tumors in orthotopic and subcutaneous xenograft tumor models and transgenic mice, as well as the growth of human tumor organoids carrying mutp53. Our results reveal that mutp53 palmitoylation is an important mechanism underlying mutp53 accumulation and GOF, and targeting FASN is a potential therapeutic strategy for cancers carrying mutp53.