Accumulating evidence has documented that STAT3 phosphorylation at Tyr705 and Ser727 jointly promotes the initiation and progression of gastric cancer. However, most reported STAT3 inhibitors have mainly focused on suppressing STAT3 phosphorylation at Tyr705 while ignoring the tumorigenic effects of phosphorylation at Ser727. Herein, we described the design, synthesis, and structure-activity relationship studies on a series of triaromatic heterocyclic derivatives as potent dual phosphorylation STAT3 inhibitors. These efforts led to the discovery of the best compound 3h (HP590) among the investigated ones, a novel, highly potent, and orally bioavailable STAT3 inhibitor possessing lower nanomolar inhibitory activity toward p-Tyr705 and p-Ser727. Target validation revealed that HP590 selectively targets STAT3 to remarkably inhibit its canonical and noncanonical activation and corresponding biological functions, thereby resulting in the growth inhibition of gastric cancer in vitro and in vivo, highlighting the therapeutic potential of dual phosphorylation STAT3 inhibitors for gastric cancer.