Background Mucus cytokines have been linked to baseline metrics of quality of life and olfactory function in patients with chronic rhinosinusitis (CRS). However, their potential utility in predicting postoperative outcomes has not been assessed. Therefore, in this study we evaluated the role of mucus cytokines in predicting 22‐item Sino‐Nasal Outcomes Test (SNOT‐22) scores after endoscopic sinus surgery (ESS) in a prospective cohort of CRS patients. Methods One hundred forty‐seven patients with CRS electing surgical therapy were enrolled in a longitudinal cohort study. Mucus was collected intraoperatively from the middle meatus and tested for interleukin (IL)‐1β, IL‐2, ‐4, ‐5, ‐6, ‐7,‐ 8, ‐9, ‐10, ‐12, ‐13, ‐17A, and ‐21; tumor necrosis factor (TNF)‐α; interferon‐γ; eotaxin; and RANTES (regulated‐on‐activation, normal T‐cell expressed and secreted) expression using a multiplex flow‐cytometric bead assay. Sixty‐two patients were followed postoperatively (average, 10.2 months) with baseline and follow‐up SNOT‐22 surveys. Stepwise multivariate linear regression was used to model relationships between baseline cytokines, phenotype, and average postoperative SNOT‐22 total and domain scores. A machine learning approach using a random forest algorithm was also used to investigate potential nonlinear relationships. Results IL‐5 was an independent predictor of postoperative total SNOT‐22 improvement (β = −8.8, p < 0.0001), whereas IL‐2 levels predicted postoperative worsening (β = 6.97, p = 0.0015). Similar relationships were also seen for postoperative SNOT‐22 domain scores. The overall model was also noted to be significant fit for the data (adjusted R 2 = 0.398, p < 0.0001). The random forest model similarly identified IL‐5, TNF‐α, IL‐13, and IL‐2 as major predictors of postoperative SNOT‐22 scores. Conclusion Mucus cytokine profiles may help identify CRS patients who are likely to obtain postoperative improvement after ESS.