Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) is a chronic inflammatory condition of the nasal and paranasal sinus mucosa with nasal polyp formation. This systematic review evaluated the efficacy and safety of biological therapies, including omalizumab, mepolizumab, and benralizumab, compared with endoscopic sinus surgery (ESS) in CRSwNP management. A literature search using the PubMed, Scopus, and Web of Science databases identified five studies that met the inclusion criteria. The studies included randomized controlled trials and observational studies assessing biological therapies or ESS in adults with CRSwNP. The primary outcomes were nasal polyp score (NPS), nasal congestion score, Sinonasal Outcome Test (SNOT-22), and adverse events. Omalizumab showed significant improvements in NPS, nasal congestion score, and SNOT-22 scores compared to placebo, with sustained effects in an open-label extension study. Mepolizumab significantly reduced SNOT-22 scores, improved lung function, and decreased blood eosinophil counts and systemic corticosteroid use in patients with severe eosinophilic asthma and CRSwNP. Benralizumab improved NPS and nasal blockage scores compared to placebo, with effects varying by comorbidities and baseline characteristics. ESS with medical therapy showed better SNOT-22 scores than medical therapy alone, though not reaching the minimal clinically important difference. Biological therapies and ESS were well tolerated, with adverse events comparable to those of the placebo. This review demonstrates the effectiveness of biological therapies and ESS in managing CRSwNP, particularly in severe cases of the disease. Further research is needed to evaluate the long-term efficacy, safety, and cost-effectiveness of these interventions in CRSwNP management.