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ΔNp63α, a member of the p53 family of transcription factors, plays a critical role in normal development and human disease. Loss of ΔNp63α expression is associated with increased cancer invasiveness and metastasis. The small GTPase Rac1 is a master regulator of cell motility, and increased Rac1 activity upregulates cell invasion in multiple human cancers. Increased cancer cell invasion associated with ΔNp63α knockdown and Rac1 activation suggests a novel mechanism by which ΔNp63α regulates tumor invasiveness through Rac1. Accordingly, we sought to delineate the effects of ΔNp63α on Rac1 phosphorylation, activation and subcellular localization. We identified a novel ΔNp63α/miR-320a/PKCᵧ signaling pathway that regulates Rac1 function via altered phosphorylation. Mechanistically, ΔNp63α inhibits cell invasion by positively regulating miR-320a, resulting in a downregulation of PKCᵧ and reduction in Rac1 phosphorylation. Moreover, ΔNp63α negatively regulates Rac1 activation by inhibiting the Rac specific GEF P-Rex1. We found that P-Rex1 is a target of ΔNp63α, and that P-Rex1 knockdown abrogated the increase in active GTP-Rac1 levels and cell invasion resulting from ΔNp63α knockdown. Finally, we showed that ΔNp63α silencing decreased nuclear Rac1 localization and increased plasma membrane Rac1 and pRac1, suggesting that ΔNp63α may serve as a critical regulator of nuclear Rac1 function. Taken together, our data indicate ΔNp63α negatively regulates Rac1 phosphorylation and GTP-binding, and modulates Rac1 localization. Since dysregulated Rac1 activity and localization have been shown to promote tumor progression, these findings suggest the ΔNp63α/Rac1 axis may be targeted to improve the effectiveness of anti-Rac1 therapies in the treatment of cancer metastasis.