Over one million new cases of non-melanoma skin cancer are diagnosed each year worldwide. The chemotherapeutic drug Cisplatin is often used as a monotherapy or in conjunction with ionizing radiation (IR) to treat squamous cell carcinoma (SCC) in patients. However, the majority of SCC cancer cases fail to respond to therapy resulting in lower response rates and higher rates of disease re-occurrence. ΔNp63α a member of the p53 transcription factor family, is overexpressed and considered oncogenic in non-melanoma skin cancer where it regulates cell survival and proliferation. TIP60 (Tat-interacting protein 60kDa), a histone acetyltransferase, has been shown to regulate cellular processes such as transcription and the DNA damage response (DDR). We previously reported that TIP60 positively regulates ΔNp63α protein levels in a catalytic-dependent manner to promote SCC proliferation. Since ΔNp63α is known to transcriptionally regulate several DDR genes and promote resistance to cisplatin, its stabilization by TIP60 may contribute to the failure of platinum-based drugs in SCC. We hypothesize that TIP60-mediated acetylation of ΔNp63α regulates its stability and transcriptional activity to modulate cisplatin uptake, the DDR response, apoptotic cell death and chemoresistance. In this project, we sought to elucidate the role of TIP60 as an upstream regulator of ΔNp63α and its involvement in conferring resistance to cisplatin. We have shown that silencing endogenous TIP60 in multiple SCC cell lines leads to a decrease in ΔNp63α transcript and protein levels, thus confirming that TIP60 positively regulates ΔNp63α. Further, we showed that increased TIP60 levels positively correlated with ΔNp63α acetylation, protein stability and cisplatin resistance. Pharmacological inhibition of TIP60 using small molecule inhibitors reduced acetylation of ΔNp63α and sensitized resistant cells to cisplatin. In addition, stable expression of TIP60 or ΔNp63α individually promoted resistance to cisplatin and reduced cell death, whereas loss of ΔNp63α and TIP60 induced G2/M arrest, increased cell death and reduced cell survival. Moreover, we demonstrated that ΔNp63α and TIP60 levels positively correlated with DNA repair capacity and negatively correlated with cisplatin-DNA adduct formation. Depletion of either TIP60 or ΔNp63α enhanced cisplatin-DNA adduct formation and significantly reduced expression of genes involved in DDR. Taken together, our data indicate that TIP60-mediated stabilization of ΔNp63α increases cisplatin resistance and provides critical insights into the mechanisms by which ΔNp63α confers cisplatin resistance through cell cycle regulation and DNA damage repair. Our findings also suggest that TIP60 inhibition could offer therapeutic benefits in overcoming cisplatin resistance in SCC and other epithelial cancers, therefore presenting it as a promising drug target for SCC cancer treatment.