Background: Outside of SINUS-24 (A Controlled Clinical Study of Dupilumab in Patients With Bilateral Nasal Polyps) and SINUS-52 (Controlled Clinical Study of Dupilumab in Patients With Nasal Polyps), there are limited data on the efficacy of dupilumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). The objective was to compare dupilumab with functional endoscopic sinus surgery (FESS) in patients with CRSwNP by assessing the change in nasal polyp and Sino-Nasal Outcome Test (SNOT-22) scores postintervention. Methods: A retrospective matched cohort study compared 54 patients who had CRSwNP treated with dupilumab with 54 patients who had CRSwNP treated with FESS; both cohorts were treated with topical corticosteroids. The primary end points were change in nasal polyp score and overall SNOT-22 score. Secondary end points were change in SNOT-22 domain scores and SNOT-22 olfaction score.Results: Patients who underwent FESS had a greater improvement in nasal polyp score (5.18 ± 2.01) compared with patients treated with dupilumab (4.27 ± 1.98, p = 0.02). There was no significant difference in terms of the change in overall SNOT-22 score. Patients treated with dupilumab had greater improvement in the extranasal rhinologic SNOT-22 domain scores (4.87 ± 3.91) compared with patients treated with FESS (2.93 ± 4.32, p = 0.02). There was a greater improvement in the SNOT-22 olfaction scores for patients treated with dupilumab (2.35 ± 2.17) compared with patients treated with FESS (1.48 ± 2.24, p = 0.04). Patients taking dupilumab were followed on average for 12.20 months and patients treated with FESS were followed for 17.90 months. Conclusion: Overall, both therapies are effective at reducing symptoms in patients with CRSwNP according to SNOT-22. Patients treated with dupilumab reported improved olfaction and decreased cough, postnasal drainage, and thick nasal drainage as compared with patients treated with FESS, while patients treated with FESS had a greater reduction in polyp burden.