Purpose: Congenital Nasolacrimal duct obstruction (CNLDO) is a relatively common problem in children with Down syndrome (DS). Probing and irrigation (PI) with monocanalicular stent intubation may be less successful than in non-DS patients, thus raising some concerns regarding the preferred treatment in this population. We aimed to analyze the surgical outcome of PI along with monocanalicular stent intubation in children with DS compared with non-DS patients. Methods: Retrospective cohort study. Thirty-five eyes of 19 children with DS and 1,472 eyes of 1,001 children without DS underwent PI-monocanalicular stent intubation as a primary treatment for CNLDO. All patients were operated on by a single surgeon at the Children's Hospital of Philadelphia between 2009 and 2020. The main outcome measure was a surgical success, defined as the resolution of symptoms after surgery. Results: A total of 1,020 patients were included, 48% females; mean age of 1.9 ± 1.4 years. The mean follow-up time was 35.0 months. The DS patients group consisted of 19 patients. Higher rates of right nasolacrimal duct obstruction and bilateral obstructions were observed in the DS group (100% vs. 73.2%; p = 0.006, and 84.2% vs. 46.8%; p = 0.001, respectively). Patients with DS had a lower success rate (57.1% vs. 92.4%; p < 0.0001). The median time to failure was 3.1 months in the DS group, and 5.2 months in the group of patients without DS. The hazard ratio comparing DS to the no-DS outcome was 6.6 (95% CI: 3.2-13.7; p < 0.001). Conclusions: CNLDO in DS is more likely to be bilateral and less likely to resolve after primary monocanalicular stent placement.