Mice with a keratinocyte-restricted deletion of the actin-polymerization promoting molecule N-WASP display cyclic hair loss and skin inflammation. Here we showed that these mice were also resistant to DMBA/TPA induced skin tumor formation. This resistance correlated with decreased expression of the senescence regulator DNMT1 and increased expression of the senescence marker p16Ink4a in N-WASP-deficient epidermis. Moreover, primary N-WASP null keratinocytes displayed a premature senescence phenotype in vitro. Expression and activation of p53, a major inducer of senescence, was not significantly altered in N-WASP-null keratinocytes. However, impairment of p53 function effectively rescued the senescence phenotype, indicating that N-WASP was an inhibitor of p53-induced senescence. Mechanistically, N-WASP regulated senescence by preventing p53-dependent degradation of the H3K9 methyltransferases G9a/GLP and the DNA methyltransferase DNMT1, which both control keratinocyte senescence. This pathway collaborated with other N-WASP-independent, senescence-promoting signaling downstream of p53 and allowed the fine tuning of p53-induced senescence by N-WASP. Collectively, these data reveal N-WASP as an inhibitor of p53-induced senescence, which might be of importance for skin tumor formation and cellular aging of keratinocytes.