<p>Current guidelines recommend the presence of type 2 inflammation as one of the indications for biologic therapy in chronic rhinosinusitis with nasal polyps (CRSwNP). Although blood eosinophil (Eos) levels are commonly used as a biomarker for type 2 inflammation, their value in predicting differential responses to biologic treatment has not been verified by high-quality evidence. We searched the PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials (Central) databases, and hand-searched Clinicaltrials.gov for all RCTs that used biologic therapies for CRSwNP. Primary outcomes included the nasal polyp score (NPS), nasal congestion score (NCS), a 22-item sino-nasal outcome test (SNOT-22) score, and loss of smell (Los) score. This study is registered with PROSPERO (CRD420251063136). This meta-analysis included 9 studies comprising 10 RCTs (<i>n</i> = 2,551), all of which were judged to be at a high risk of selection bias. The results showed that when compared with placebo treatment, biologic therapy significantly improved all outcome measures, including the NPS, NCS, SNOT-22 score, and LoS score, —regardless of baseline Eos levels. However, inter-subgroup comparisons clearly showed that both the Eos ≥ 150 cells/µL and Eos ≥ 300 cells/µL groups had significantly greater improvements in their NPS and NCS when compared with the Eos &lt; 150 cells/µL group (<i>p</i> &lt; 0.05). In contrast, improvements in the SNOT-22 scores and LoS scores were comparable across all subgroups, with no statistically significant differences observed. An exploratory analysis suggested that at the Eos ≥ 300 cells/µL threshold, anti-IL-4Rα monoclonal antibodies may be superior to anti-IL-5 monoclonal antibodies for improving the NPS and NCS (<i>p</i> &lt; 0.05). Although biologics demonstrate efficacy in the overall CRSwNP population, a baseline blood eosinophil count ≥ 150 cells/µL pinpoints the patient subgroup with a superior response.</p>