Among tea polyphenols, the anti-initiating properties of polymeric black tea polyphenols (PBPs), the most abundant polyphenols in black tea, are poorly elucidated. Hence, this study was undertaken to investigate the effects of PBP extract on the induction of phase II enzymes. PBP extract induced transcriptional up-regulation of phase II enzymes in liver and lungs by increasing Nrf2-mediated antioxidant-responsive element (ARE) binding. PBP extract did not alter Nrf2 or Keap1 at the transcriptional level but may have increased their levels by posttranslational modifications such as phosphorylation and decreased ubiquitination. PKC and PI3-kinase-mediated phosphorylation of Nrf2 seems to be critical for the release of Nrf2 from Keap1 and its subsequent nuclear translocation. mafK was found to be the heterodimeric partner of Nrf2 for binding to ARE sequences in liver upon PBP extract pretreatment. Differences in phosphorylation, activation of cellular kinases, and speculated heterodimeric binding partners of Nrf2 by PBP extract in hepatic and pulmonary tissues suggested the possibility of tissue-specific differences in the activation of Nrf2. Thus, we conclude that the pathway of PBP extract-induced ARE activity involves the activation of Nrf2 through phosphorylation by PKC and PI3-kinases in hepatic cells, which is critical for the increased stability of Nrf2 upon release from Keap1 and nuclear translocation, respectively.