Abstract: Breast cancer (BC) remains a significant challenge to women’s health, and identifying effective molecular targets is crucial for therapeutic advancement. Krüppel-like factor 5 (KLF5), an oncogenic transcription factor, is highly expressed in BC, yet its development as a therapeutic target has been hindered by its intrinsically disordered structure. In this study, we identified Brevilin A (BrA), a natural sesquiterpenoid from Centipeda minima, as a potent of KLF5 degrader. We demonstrated that BrA directly binds to KLF5 and promotes its ubiquitin-mediated degradation through the E3 ligase WWP2. BrA significantly inhibited BC cell proliferation and induced severe mitochondrial dysfunction and endoplasmic reticulum (ER) stress, as evidenced by reduced mitochondrial respiration and activation of the PERK-EIF2α pathway. Mechanistically, BrA enhanced the recruitment of WWP2 to KLF5, leading to its polyubiquitination and subsequent proteasomal degradation. KLF5 overexpression effectively rescued the mitochondrial and ER homeostasis disrupted by BrA, whereas KLF5 knockdown rendered cells insensitive to BrA-induced cytotoxicity. In vivo studies using zebrafish and nude mouse xenograft models confirmed that BrA suppressed tumor growth by downregulating KLF5 and its downstream metabolic effectors. Collectively, our findings reveal that BrA exerts antitumor effects by promoting WWP2-mediated ubiquitination and degradation of KLF5, thereby disrupting mitochondrial and ER integrity, highlighting its potential as a natural lead compound for BC treatment.