Cisplatin chemoresistance is a clinical problem that leads to treatment failure in various human epithelial cancers. Members of tumor protein (TP) p53 family play various critical roles in the multiple molecular mechanisms underlying the chemoresistance of tumor cells. However, the in-depth mechanisms of the cellular response to cisplatin-induced cell death are still under thorough investigation. We previously showed that squamous cell carcinoma (SCC) cells exposed to cisplatin display an ATM-dependent phosphorylation of ΔNp63α, leading to a specific function of the phosphorylated (p)-ΔNp63α transcription factor in cisplatin-sensitive tumor cells. We further found that SCC cells expressing non-p-ΔNp63α-S385G became cisplatin-resistant. Using quantitative mass-spectrometry of protein complexes labeled with isobaric tags, we showed that TP53 and ΔNp63α are involved in numerous protein-protein interactions, which are likely to be implicated in the response of tumor cells to cisplatin exposure. We found that p-ΔNp63α binds to the splicing complex, leading to repression of mRNA splicing and activation of ACIN1-mediated cell death pathway. In contrast to p-ΔNp63α, non-p-ΔNp63α fails to bind the critical members of the splicing complex, thereby leading to activation of RNA splicing and reduction of cell death pathway. Overall, our studies provide an integrated proteomic platform in making a case for the role of the p53/p63 interactome in cisplatin chemoresistance.