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In response to genotoxic stress, multiple kinase signaling cascades are activated, many of them directed towards the tumor suppressor p53, which coordinates the DNA damage response (DDR). Defects in DDR pathways lead to an accumulation of mutations that can promote tumorigenesis. Emerging evidence implicates multiple members of the NimA-related kinase (NEK) family (NEK1, NEK10, and NEK11) in the DDR. Here, we describe a function for NEK10in the regulation of p53 transcriptional activity through tyrosine phosphorylation. NEK10loss increases cellular proliferation by modulating the p53-dependent transcriptional output. NEK10directly phosphorylates p53 on Y327, revealing NEK10’sunexpected substrate specificity. A p53 mutant at this site (Y327F) acts as a hypomorph, causing an attenuated p53-mediated transcriptional response. Consistently, NEK10-deficient cells display heightened sensitivity to DNA-damaging agents. Further, a combinatorial score of NEK10and TP53-target gene expression is an independent predictor of a favorable outcome in breast cancers.