Type 2 diabetes (T2D) in developed countries have a prevalence of 11% with diabetic foot infections as the most common cause of hospitalization and amputation. To achieve healing of the diabetic foot ulcer wounds, appropriate dressings are essential and their effectiveness can be enhanced with nanoparticles, nevertheless ideal combinations of dressing composition and nanodrugs require further testing in humans. We have developed a calcium alginate dressings with ZnO nanoparticles (CAZnODs) for the treatment of diabetic foot ulcers in human patients. To test the efficacy of CAZnODs we designed a randomized controlled clinical experiment on 26 T2D patients with foot ulcers. The patients were randomized into two groups: G1 treatment with calcium alginate with NPs (G1; n = 16), and group 2 received the treatment without NPs (G2, n = 10). The bandage change was performed every 48 h The duration of the protocol was established at 10 weeks. Here, we report healing was achieved in patients, with 75% wound closure in G1 under treatment with NPs of calcium alginate versus 71% in G2 (calcium alginate without NPs) (p = 0.011). The average healing time was 48 days in G1 and 72 days in G2. Our data shows that CAZnODs were well tolerated and did not interfere with the wound healing process. The final wound area and time of healing support the hypothesis that the use of calcium alginate dressings with nanoparticles may induce better tissue regeneration while avoiding T2D complications such as secondary infections.