Mucus plugging constitutes a nutrient‐rich nidus for a bacterial infection that has long been recognized as a potent stimulus for neutrophilic airway inflammation driving progressive lung damage in people with cystic fibrosis (CF). However, mucus plugging and neutrophilic inflammation are already present in many infants and young children with CF even in the absence of detectable bacterial infection. A series of observational studies in young children with CF, as well as investigations in animal models with CF‐like lung disease support the concept that mucus plugging per se can trigger inflammation before the onset of airways infection. Here we review emerging evidence suggesting that activation of the interleukin‐1 (IL‐1) signaling pathway by hypoxic epithelial cell necrosis, leading to the release of IL‐1α in mucus‐obstructed airways, may be an important mechanistic link between mucus plugging and sterile airway inflammation in early CF lung disease. Furthermore, we discuss recent data from preclinical studies demonstrating that treatment with the IL‐1 receptor (IL‐1R) antagonist anakinra has anti‐inflammatory as well as mucus modulating effects in mice with CF‐like lung disease and primary cultures of human CF airway epithelia. Collectively, these studies support an important role of the IL‐1 signaling pathway in sterile neutrophilic inflammation and mucus hypersecretion and suggest inhibition of this pathway as a promising anti‐inflammatory strategy in patients with CF and potentially other muco‐obstructive lung diseases.