In this paper, we report on the validation of an autonomous drone-based delivery system equipped with a smart capsule for the transportation of blood products in urban areas. The influence of some thermo-mechanical parameters, such as altitude, acceleration/deceleration, external temperature and humidity, on the specimens’ integrity were analyzed. The comparison of the results carried out by hemolytic tests, performed systematically on samples before and after each drone flight, clearly demonstrated that the integrity of blood is preserved and no adverse effects took place during the transport; these results can be addressed to the smart-capsule properties, which allows integrating real-time quality monitoring and control of the temperature experienced by blood products and mechanical vibrations. In addition, we demonstrated this transport system reduces the delivery time considerably. A risk analysis (i.e., HFMEA) was applied to all delivery processes to assess possible criticalities. To the best of our knowledge, this is the first time a drone-based delivery system of blood products in an urban area has been validated to be employed in a future clinical scenario.