Dupilumab, omalizumab, mepolizumab, and benralizumab have demonstrated good efficacy and safety in the treatment of severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) in phase 3 randomised controlled trials (RCTs). With recent regulatory approvals, there has been a surge in real-world studies (RWSs). This systematic review and meta-analysis aimed to summarise the efficacy and safety of these four biologics in real-world settings. Primary outcomes were nasal polyp score and sino-nasal outcome test-22 score. Secondary outcomes included smell identification test score, loss of smell score, nasal congestion score, overall nasal symptom score, treatment response, and adverse events (AEs) prompting discontinuation. Efficacy outcomes at 4, 6, 12, and over 12 months were summarised, and meta-analyses of mean changes from baseline were conducted. Sixty-four RWSs involving 3921 patients were included. Significant improvements in clinical outcomes were observed at most follow-up time points, with dupilumab showing particularly notable effects. The efficacy observed in these RWSs was superior to that demonstrated in phase 3 RCTs. All biologics exhibited low discontinuation rates due to AEs. Overall, biologic treatments for CRSwNP in real-world settings demonstrate strong efficacy and good safety. However, the limitations in current RWSs highlight the need for long-term, high-quality multicentre prospective studies and comprehensive healthcare database analyses.