WWP1 E3 ubiquitin ligase has previously been shown to be frequently amplified and overexpressed in prostate and breast cancers. However, the mechanism of WWP1 action is still largely unknown. p63, a member of the p53 family of transcription factors, has an important function in tumor development by regulating apoptosis. Using alternative promoters, p63 can be expressed as ΔNp63 and TAp63. Increasing evidence suggests that TAp63 sensitizes cells to apoptosis but ΔNp63 has an opposite function. In this study, we show that WWP1 binds, ubiquitinates, and destructs both ΔNp63α and TAp63α. The protein–protein interaction occurs between the PY motif of p63 and the WW domains of WWP1. The knockdown of WWP1 by siRNA increases the endogenous ΔNp63α level in the MCF10A and 184B5 immortalized breast epithelial cell lines and confers resistance to doxorubicin-induced apoptosis. On the other hand, the knockdown of WWP1 increases the endogenous level of TAp63α, induces apoptosis, and increases sensitivity to doxorubicin and cisplatin in the HCT116 colon cancer cell line in a p53-independent manner. Finally, we found that DNA damage chemotherapeutic drugs induce WWP1 mRNA and protein expression in a p53-dependent manner. These data suggest that WWP1 may have a context-dependent role in regulating cell survival through targeting different p63 proteins for degradation.