The environmental impact of plastics is worsened by their inadequate end-of-life disposal, leading to the ubiquitous presence of micro- (MPs) and nanosized (NPs) plastic particles. MPs and NPs are thus widely present in water and air and inevitably enter the food chain, with inhalation and ingestion as the main exposure routes for humans. Many recent studies have demonstrated that MPs and NPs gain access to several body compartments, where they are taken up by cells, increase the production of reactive oxygen species, and lead to inflammatory changes. In most tissues, resident macrophages engage in the first approach to foreign materials, and this interaction largely affects the subsequent fate of the material and the possible pathological outcomes. On the other hand, macrophages are the main organizers and controllers of both inflammatory responses and tissue repair. Here, we aim to summarize the available information on the interaction of macrophages with MPs and NPs. Particular attention will be devoted to the consequences of this interaction on macrophage viability and functions, as well as to possible implications in pathology.