A catalyst-free three-component domino reaction was developed for the synthesis of benzothiophene fused pyrrolidones bearing a CF3 group for the first time. The notable advantages of this strategy over the existing methods include the use of water as a solvent at room temperature, transition metal-free conditions, a broad substrate scope, and easy scale-up synthesis. More importantly, the benzothiophene derivatives have been found to show potent anticancer activities using the Cell Counting Kit-8 (CCK-8) assay.