Sertraline sensitized drug‐resistant gastric cancer cells to chemotherapyModified sertraline derivatives (trans‐6d) showed improved potency (IC50 of 5.20 μM)Apoptosis induction and cell cycle arrest were the primary mechanisms of actionSertraline and its derivatives downregulated the PI3K/Akt/mTOR pathway, contributing to cell deathThe study supports the potential repurposing of sertraline as a chemosensitizer in drug‐resistant gastric cancer treatment. This evidence concerns the gene AKT1 and gastric cancer.