Oxidative stress and impaired antioxidant defense are believed to be contributors to the cardiovascular aging process. The transcription factor NF-E2 related factor 2 (Nrf2) plays a key role in orchestrating cellular antioxidant defenses and maintaining redox homeostasis. Our previous study showed that Exendin-4, a GLP-1 analogue, alleviates angiotensin II (Ang II)-induced VSMC senescence by inhibiting Rac1 activation via cAMP/PKA. The objective of this study is to investigate if Nrf2 mediates the anti-senescent effect of Exendin-4 in Ang II-induced VSMCs. Here we report that Exendin-4 triggered Nrf2 nuclear translocation, a downstream target of cAMP responsive element-binding protein (CREB) and expressions of antioxidant genes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO-1) in a dose- and time-dependent manner. In addition, knock-down of Nrf2 attenuated the inhibitory effects of Exendin-4 on Ang II-induced superoxidant generation and VSMC senescence. PKA/CREB pathway participated in the upregulations of HO-1 and NQO-1 induced by Exendin-4. Notably, our study revealed that Exendin-4 dose-dependently increased the acetylation of Nrf2 and the the recruitment of transcriptional coactivator CREB binding protein (CBP) to Nrf2. The Exendin-4-induced Nrf2 transactivation was diminished in the presence of CBP siRNA. Microscope imaging of Nrf2 as well as immunoblotting for Nrf2 showed that the Exendin-4-evoked Nrf2 acetylation favored its nuclear retention. Importantly, CBP silencing attenuated the suppressing effects of Exendin-4 on Ang II-induced VSMC senescence and superoxidant production. In conclusion, these results provide a mechanistic insight into how Nrf2 signaling mediates the anti-senescent and anti-oxidative effects induced by Exendin-4 in VSMCs.