Constitutive activation of STAT3 has been found in a wide variety of cancers and demonstrated as a very attractive therapeutic target. Disrupting both acetylation and phosphorylation of STAT3 protein was hypothesized to greatly deactivate STAT3, therefore, treating cancers. To demonstrate the hypothesis, two series of novel resveratrol-caffeic acid hybrids were designed aiming to regulate both acetylation and phosphorylation of STAT3 protein, which is also the first report of the synthetic inhibitors simultaneously regulating two biological reactions of STAT3 to our knowledge. Most of these compounds were demonstrated with preferential antitumor activity with low IC50 values against two cancer cell lines. Particularly, compound 7d was found as an excellent STAT3 inhibitor with over 50-fold better potency than resveratrol and caffeic acid. Meanwhile, the novel derivatives significantly inhibited the proliferation and induced the apoptosis of tumor cells. Molecular docking further disclosed the binding modes of STAT3 with the inhibitors. In addition, compound 7d orally and significantly suppressed breast cancer 4T1 xenograft tumor growth in vivo, indicating its great potential as an efficacious drug candidate for human cancer therapy.