Graphene-based materials (GBMs) have promising applications in various sectors, including pulmonary nanomedicine. Nevertheless, the influence of GBM physicochemical characteristics on their fate and impact in lung has not been thoroughly addressed. To fill this gap, we investigated the biological response, distribution and bio-persistence of four different GBMs in mouse lungs up to 28 days after single oropharyngeal aspiration. None of the GBMs, varying in size (large vs. small) and carbon to oxygen ratio as well as thickness (few-layers graphene (FLG) vs. thin graphene oxide (GO)), induced a strong pulmonary immune response. However, recruited neutrophils internalised nanosheets better and degraded GBMs faster than macrophages, revealing their crucial role in the elimination of small GBMs. In contrast, large GO sheets induced more damages due to a hindered degradation and long-term persistence in macrophages. Overall, small dimensions appeared to be a leading feature in the design of safe GBM pulmonary nanovectors due to an enhanced degradation in phagocytes and a faster clearance from the lungs for small GBMs. Thickness played also an important role, since decreased material loading in alveolar phagocytes and faster elimination were found for FLGs compared to thinner GOs. These results are important for designing safer-by-design GBMs for biomedical applications.