Although STK11 (LKB1) mutation is a major mediator of lung cancer progression, targeted therapy has not been implemented due to STK11 mutations being loss-of-function. Here, we report that targeting the Na(+)/K(+)-ATPase (ATP1A1) is synthetic lethal with STK11 mutations in lung cancer. The cardiac glycosides (CGs) digoxin, digitoxin and ouabain, which directly inhibit ATP1A1 function, exhibited selective anticancer effects on STK11 mutant lung cancer cell lines. Restoring STK11 function reduced the efficacy of CGs. Clinically relevant doses of digoxin decreased the growth of STK11 mutant xenografts compared to wild type STK11 xenografts. Increased cellular stress was associated with the STK11-specific efficacy of CGs. Inhibiting ROS production attenuated the efficacy of CGs, and STK11-AMPK signaling was important in overcoming the stress induced by CGs. Taken together, these results show that STK11 mutation is a novel biomarker for responsiveness to CGs. Inhibition of ATP1A1 using CGs warrants exploration as a targeted therapy for STK11 mutant lung cancer.