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Background and Purpose: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and severe hypoxaemia. We investigated whether genetic deficit or blockade of calcium-activated potassium (K Ca3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS. Experimental Approach: K Ca3.1 channel knockout (Kccn4 -/-) mice were exposed to ventilator-induced lung injury. Control mice exposed to ventilator-induced lung injury were treated with the K Ca3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO 2/FiO 2 ratio), lung compliance, lung wet-to-dry weight and protein and cytokines in bronchoalveolar lavage fluid (BALF). Key Results: Ventilator-induced lung injury resulted in lung oedema, decreased lung compliance, a severe drop in PaO 2/FiO 2 ratio, increased protein, neutrophils and tumour necrosis factor-alpha (TNF-α) in BALF from wild-type mice compared with Kccn4 -/- mice. Pretreatment with senicapoc (10–70 mg·kg −1) prevented the reduction in PaO 2/FiO 2 ratio, decrease in lung compliance, increased protein and TNF-α. Senicapoc (30 mg·kg −1) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30 mg·kg −1 senicapoc also improved the PaO 2/FiO 2 ratio and reduced lung injury score and neutrophils in the BALF compared with vehicle-treated mice. In human lung epithelial cells, senicapoc decreased TNF-α-induced permeability. Conclusions and Implications: Genetic deficiency of K Ca3.1 channels and senicapoc improved the PaO 2/FiO 2 ratio and decreased the cytokines after a ventilator-induced lung injury. Moreover, senicapoc directly affects lung epithelial cells and blocks neutrophil infiltration in the injured lung. These findings indicate that blocking K Ca3.1 channels is a potential treatment in ARDS-like disease.