Cooperation between neutrophils and macrophages is essential to innate immunity. Though they share origins, their distinct roles make them complementary in fighting pathogens and regulating inflammation. However, dysregulation can drive chronic inflammation and autoimmune disease, making therapeutic targeting highly challenging. Broad suppression of these cells is risky; instead, precision strategies are needed to modulate their dual roles in promoting and resolving inflammation. Aging further complicates this balance, as impaired neutrophil and macrophage functions-alongside microbiota alterations-contribute to inflammaging and immune dysfunction. Recent advances in technology offer opportunities to explore these interactions in physiologically relevant contexts, paving the way for targeted interventions that restore immune homeostasis without compromising defense mechanisms. This article highlights the need for nuanced approaches to harness neutrophil-macrophage cooperation for therapeutic benefit.