Selenium is an essential micronutrient, known for its cancer prevention properties, that is incorporated into a class of selenocysteine-containing proteins (selenoproteins). The human genome encodes 25 selenoproteins which play diverse roles in redox homeostasis, thyroid hormone metabolism, endoplasmic reticulum function and selenium transport. Selenoprotein H (seph) is a recently identified nucleolar oxidoreductase with DNA-binding properties whose function is not well understood. Here, we discover that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impaired redox balance by reducing the levels of ascorbate and methionine, whilst increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induced an inflammatory response and activated the p53 pathway. Consequently, loss of seph rendered larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, these studies establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.