Background: To compare the safety and efficacy between endoscopic sinus surgery and different biologics in treating chronic rhinosinusitis with nasal polyps in adults by reviewing the existing clinical trials.Methods: Data extraction and risk of bias assessment were conducted by 2 independent reviewers according to the PRISMA recommendations and any disagreement was resolved by a third investigator. Outcomes were measured through a random‐effects model. We searched Embase, Web of Science, MEDLINE, Cochrane, and other relevant sources from its inception to April 30, 2022. We included randomized controlled trials(RCTs) involving endoscopic sinus surgery (ESS) or biologics in treating adult patients with chronic rhinosinusitis with nasal polyps. Studies involving other miscellaneous diseases, non‐RCT design, and insufficient participants or follow‐up were excluded.Results: In this systematic review, five RCTs and 1748 patients were included. All the biologics, as well as ESS, could significantly improve key nasal outcomes in CRSwNP both at 6 months and 1 year. Dupilumab exhibited better efficacy than ESS in improving SNOT‐22 scores at one year. However, ESS showed superiority over three biologics in improving nasal congestion scores (NCS) at two various time points, except for better efficacy of Dupilumab at 1 year. For the loss of smell scores, a greater improvement was observed in the Dupilumab cohort compared with other biologics and even ESS counterparts. Safety analysis showed no significant difference between the ESS cohort and biologic treatment.Conclusions: In summary, ESS showed comparable improvement in quality of life and symptoms to Omalizumab, Mepolizumab, and Benralizumab. Dupilumab seems to be more effective than ESS in selected items, whereas head‐to‐head trials and real‐world studies are urgent to compare their efficacy. Our findings also showed that biologics could be applied as alternative or adjuvant therapy for uncontrolled severe CRSwNP.