Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a type 2 pattern of inflammation resulting in the production of some cytokines. Dupilumab radically changes the treatment of CRSwNP, but, considering its recent approval, it may be useful to evaluate its safety profile in a real-world setting. This work aimed to prospectively highlight the effectiveness and safety profile of dupilumab in patients with CRSwNP enrolled in the Otorhinolaryngology Unit of the University Hospital of Messina. An observational cohort study was carried out considering all patients treated with dupilumab. A descriptive analysis was conducted reporting all demographic characteristics, endoscopic evaluations, and symptom conditions. A total of 66 patients were treated with dupilumab, but three patients were excluded due to a lack of adherence during the observational period. A statistically significant reduction in the Sino-Nasal Outcome Test 22 (SNOT-22) and nasal polyps score (NPS) was shown at the 6th and 12th months compared to baseline values (SNOT-22, −37 and −50, p < 0.001 for both comparisons; NPS, −3 and −4, p < 0.001 for both comparisons). During the follow-up, eight patients (12.7%) had a reaction at the site of injection, and seven (11.1%) had transient hypereosinophilia. Given the optimal treatment response and the minimal adverse effects observed, clinicians should consider dupilumab a safe and effective treatment. Further studies are necessary to better understand the long-term effects.