Active re‐absorption of Na⁺ across the alveolar epithelium is essential to maintain lung fluid balance. Na⁺ entry at the luminal membrane is predominantly via the amiloride‐sensitive Na⁺ channel (ENaC) down its electrochemical gradient. This gradient is generated and maintained by basolateral Na⁺ extrusion via Na⁺,K⁺‐ATPase an energy‐dependent process. Several kinases and factors that activate them are known to regulate these processes; however, the role of AMP‐activated protein kinase (AMPK) in the lung is unknown. AMPK is an ultra‐sensitive cellular energy sensor that monitors energy consumption and down‐regulates ATP‐consuming processes when activated. The biguanide phenformin has been shown to independently decrease ion transport processes, influence cellular metabolism and activate AMPK. The AMP mimetic drug 5‐aminoimidazole‐4‐carboxamide‐1‐β‐d‐ribofuranoside (AICAR) also activates AMPK in intact cells. Western blotting revealed that both the α1 and α2 catalytic subunits of AMPK are present in Na⁺ transporting H441 human lung epithelial cells. Phenformin and AICAR increased AMPK activity in H441 cells in a dose‐dependent fashion, stimulating the kinase maximally at 5–10 mm (P= 0.001, n= 3) and 2 mm (P < 0.005, n= 3), respectively. Both agents significantly decreased basal ion transport (measured as short circuit current) across H441 monolayers by approximately 50% compared with that of controls (P < 0.05, n= 4). Neither treatment altered the resistance of the monolayers. Phenformin and AICAR significantly reduced amiloride‐sensitive transepithelial Na⁺ transport compared with controls (P < 0.05, n= 4). This was a result of both decreased Na⁺,K⁺‐ATPase activity and amiloride‐sensitive apical Na⁺ conductance. Transepithelial Na⁺ transport decreased with increasing concentrations of phenformin (0.1–10 mm) and showed a significant correlation with AMPK activity. Taken together, these results show that phenformin and AICAR suppress amiloride‐sensitive Na⁺ transport across H441 cells via a pathway that includes activation of AMPK and inhibition of both apical Na⁺ entry through ENaC and basolateral Na⁺ extrusion via the Na⁺,K⁺‐ATPase. These are the first studies to provide a cellular signalling mechanism for the action of phenformin on ion transport processes, and also the first studies showing AMPK as a regulator of Na⁺ absorption in the lung.