The YAP1 signaling pathway is not only an oncogenic signaling pathway but also an important therapeutic target in cancer. Plumbagin (PLB) is a natural naphthoquinone that exhibits anticancer potential in diverse cancers. However, the half-life of PLB in vivo is short. Here, we show that loading PLB with zeolitic imidazolate framework-90 (ZIF-90) (PLB@ZIF-90) significantly prolongs the PLB half-life in vitro and in vivo and significantly increases the PLB concentration in tumor tissues compared to free PLB. Importantly, PLB@ZIF-90 more dramatically suppressed gastric cancer growth and lung metastasis in animal models than free PLB. In addition, we demonstrated that PLB suppresses YAP1 levels and nuclear translocation by promoting YAP1 phosphorylation, thereby reducing the binding level of YAP1 and TEAD1 in the nucleus and ultimately inhibiting YAP1/TEAD1 complex-regulated oncogene expression. Notably, the inhibitory effect of PLB on gastric cancer was confirmed in PDX models expressing different levels of YAP1. In summary, our data indicate that PLB exerts antigastric cancer effects by suppressing the YAP1 signaling pathway, that ZIF-90 is a useful carrier for PLB in vivo delivery and that loading PLB with ZIF-90 is a useful strategy for cancer targeted therapy.