We evaluate the early and late safety and efficacy of silver nanoparticle (AgNPs) in wound healing after circumcision. This multicenter prospective comparative non-randomized observational study compares wound dressing with AgNPs (group A) vs. gentamicin cream (group B). Follow-up included objective evaluation at 10 and 30 days by the Southampton Scoring System (SSS) and Stony Brook Scar Evaluation Scale (SBSES). We enrolled 392 males: 194 in group A, and 198 in group B. At 10 days follow-up, in group A, the SSS scale was grade 1 in 49.5% and grade 2 in the remaining; meanwhile, in group B, grade 1 was in 58%, grade 2 in 34.3%, and grade 4 in 7.6%. At 30 days follow-up, grade 1 healing was 97.4% and 98.4% in group A and B, respectively. At 10 days follow-up, the mean SBSES score was 3.58 and 3.69 in group A and B, respectively; while at 30 days follow-up, 4.81 and 4.76 in group A and B, respectively. Only in group B did 7.6% of males have antibiotic therapy due to pus discharge. No patients needed surgical wound revision. AgNPs led to a late but safer healing, they were non-inferior to the antibiotic cream wound dressing efficacy, and they avoided pus discharge and the need for oral antibiotics due to their polymer material.