Endoprostheses are prone to tribological wear and biological processes that lead to the release of particles, including aluminum nanoparticles (Al NPs). Those particles can diffuse into circulation. However, the toxic effects of NPs on platelets have not been comprehensively analyzed. The aim of our work was to investigate the impact of Al NPs on human platelet function using a novel quartz crystal microbalance with dissipation (QCM-D) methodology. Moreover, a suite of assays, including light transmission aggregometry, flow cytometry, optical microscopy and transmission electron microscopy, were utilized. All Al NPs caused a significant increase in dissipation (D) and frequency (F), indicating platelet aggregation even at the lowest tested concentration (0.5 µg/mL), except for the largest (80 nm) Al NPs. A size-dependent effect on platelet aggregation was observed for the 5–20 nm NPs and the 30–50 nm NPs, with the larger Al NPs causing smaller increases in D and F; however, this was not observed for the 20–30 nm NPs. In conclusion, our study showed that small (5–50 nm) Al NPs caused platelet aggregation, and larger (80 nm) caused a bridging–penetrating effect in entering platelets, resulting in the formation of heterologous platelet–Al NPs structures. Therefore, physicians should consider monitoring NP serum levels and platelet activation indices in patients with orthopedic implants.