In this work, thermoplastic polyurethane (TPU) composites incorporated with 1.0 wt% Cu particles were synthesized by the melt blending method. The effect of the incorporated copper particle size on the antibacterial, thermal, rheological, and mechanical properties of TPU was investigated. The obtained results showed that (i) the addition of copper particles increased the thermal and mechanical properties because they acted as co-stabilizers of polyurethane (PU) (ii) copper nanoparticles decreased the viscosity of composite melts, and (iii) microparticles > 0.5 µm had a tendency to easily increase the maximum torque and formation of agglomerates. SEM micrographics showed that a good mixture between TPU and copper particles was obtained by the extrusion process. Additionally, copper-TPU composite materials effectively inhibited the growth of the Gram-negative Escherichia coli and the Gram-positive Staphylococcus aureus. Considering that the natural concentration of copper in the blood is in the range of 0.7–0.12 mg/L and that the total migration value of copper particles from TPU was 1000 times lower, the results suggested that TPU nanocomposites could be adequately employed for biomedical applications without a risk of contamination.