COPD is a seriously disabling respiratory condition that inexorably progresses to disability and mortality. It affects approximately 10% of the population globally with a greater prevalence at advanced ages. Airway bacterial infections complicate the disease course in most COPD patients, leading to increased symptoms, more rapid decline in lung function, acute exacerbations and reduced quality of life. With increasing bacterial resistance to antibiotics and adverse effects of conventional treatments, new effective non-antibiotic antimicrobial therapies are urgently needed to manage COPD. Hypoxia-inducible factor (HIF)-1α is an important transcriptional regulator of cellular responses to hypoxia, oxidants and inflammation, and is overexpressed in the lungs of COPD patients. Recent evidence shows that increased HIF-1α expression can upregulate the platelet-activating factor receptor (PAFR) on the airway epithelial surface that is increased in smokers and particularly COPD patients. The receptor is utilized by PAFR-dependent bacteria (Streptococcus pneumoniae, Haemophilus influenzae and Pseudomonas aeruginosa) to induce infection in both the respiratory and gastrointestinal (GI) tracts. However, the importance and mechanism of HIF-1α in augmenting PAFR-dependent bacterial infections in COPD are poorly understood. Here, we review the evidence for the roles of local tissue hypoxia-induced inflammation, HIF-1α and PAFR in facilitating bacterial infections in COPD. Blocking PAFR may provide a novel antimicrobial approach to manage bacterial infections in COPD.