Aberrant activation of eIF4E contributes to gastric cancer growth and resistance. MAPK-interacting kinases (MNKs) regulate eIF4E phosphorylation and activity in tumor but not normal cells and are potentially safe targets for the treatment of various cancers. Our work reveals that tomivosertib, a potent and highly selective dual MNK1/2 inhibitor, preferentially sensitizes gastric cancer to chemotherapy via suppressing MNK-eIF4E-β-catenin. We firstly demonstrate that tomivosertib displays higher efficacy than other MNK inhibitors in inhibiting gastric cancer cells. In addition, tomivosertib significantly augments the inhibitory effects of 5-FU and paclitaxel but not everolimus, suggesting that tomivosertib preferentially sensitizes gastric cancer to chemotherapy. We next show that eIF4E overexpression and phosphorylation coordinately regulate β-catenin signaling in gastric cancer. Rescue studies confirm that tomivosertib inhibits gastric cancer via targeting MNK-eIF4E-β-catenin. Finally, we demonstrate that the in vitro functional and mechanism observations are translatable to in vivo gastric cancer model in mice. Tomivosertib is now in Phase 2 clinical trials. Our study provides preclinical evidence to initialize clinical trials for gastric cancer using tomivosertib in combination with chemotherapy.