The anti-cancer drug cisplatin kills cells by damaging DNA and inducing apoptosis. Understanding the detailed mechanisms by which cancer cells respond to cisplatin has the potential to improve substantially platinum-based therapy. Post-translational modification of histones alters chromatin structure, facilitating the binding of nuclear factors that mediate DNA repair, transcription, and other processes. In the present study, we have investigated the effects of cisplatin treatment on histone post-translational modification in cancer cells. We discovered that specific phosphorylation of histone H3 at Ser-10, mediated by the p38 MAPK pathway, is induced in response to cisplatin treatment. In addition, hyperacetylation of histone H4 was caused by drug treatment. These findings revealed a link between cisplatin administration and chromosomal structural alterations, providing mechanistic information about how cells respond to platinum-induced stress.