Neutrophils represent the primary defense against microbial threats playing a pivotal role in maintaining tissue homeostasis. This review examines the multifaceted involvement of neutrophils in periodontitis, a chronic inflammatory condition affecting the supporting structures of teeth summarizing the contribution of neutrophil dysfunction in periodontitis and periodontal-related comorbidities. Periodontitis, a pathological condition promoted by dysbiosis of the oral microbiota, is characterized by the chronic inflammation of the gingiva and subsequent tissue destruction. Neutrophils are among the first immune cells recruited to the site of infection, releasing antimicrobial peptides, enzymes, and reactive oxygen species to eliminate pathogens. The persistent inflammatory state in periodontitis can lead to aberrant neutrophil activation and a sustained release of proinflammatory mediators, finally resulting in tissue damage, bone resorption, and disease progression. Growing evidence now points to the correlation between periodontitis and systemic comorbidities. Indeed, the release of inflammatory mediators, immune complexes, and oxidative stress by neutrophils, bridge the gap between local and systemic immunity, thus highlighting neutrophils as key players in linking periodontal inflammation to chronic conditions, including cardiovascular diseases, diabetes mellitus, and rheumatoid arthritis. This review underscores the crucial role of neutrophils in the pathogenesis of periodontitis and the complex link between neutrophil dysfunction, local inflammation, and systemic comorbidities. A comprehensive understanding of neutrophil contribution to periodontitis development and their impact on periodontal comorbidities holds significant implications for the management of oral health. Furthermore, it highlights the need for the development of novel approaches aimed at limiting the persistent recruitment and activation of neutrophils, also reducing the impact of periodontal inflammation on broader health contexts, offering promising avenues for improved disease management and patient care.