In recent years, increasing attention has been paid to the role of neutrophils in cardiovascular (CV) disease (CVD) with evidence supporting their role in the initiation, progression, and rupture of atherosclerotic plaque. Although these cells have long been considered as terminally differentiated cells with a relatively limited spectrum of action, recent research has revealed intriguing novel cellular functions, including neutrophil extracellular trap (NET) generation and inflammasome activation, which have been linked to several human diseases, including CVD. While most research to date has focused on the role of neutrophils in coronary artery and cerebrovascular diseases, much less information is available on lower limb peripheral artery disease (PAD). PAD is a widespread condition associated with great morbidity and mortality, though physician and patient awareness of the disease remains low. To date, several studies have produced some evidence on the role of certain biomarkers of neutrophil activation in this clinical setting. However, the etiopathogenetic role of neutrophils, and in particular of some of the newly discovered mechanisms, has yet to be fully elucidated. In the future, complementary assessment of neutrophil activity should improve CV risk stratification and provide personalized treatments to patients with PAD. This review aims to summarize the basic principles and recent advances in the understanding of neutrophil biology, current knowledge about the role of neutrophils in atherosclerosis, as well as available evidence on their role of PAD.