Objective To analyze the diagnostic value of serum interleukin-9, human cartilage glycoprotein 39, and interleukin-31 in the diagnosis of chronic spontaneous urticaria. Methods Ninety patients with active CSU admitted to Department of Dermatology of our hospital from November 2022 to October 2023 were sampled as the observation group, and the patients with active CSU were subdivided into three groups of mild, moderate, and severe according to the 7-day urticaria activity score. CSU patients who entered the quiescent phase of the disease after 4 weeks of treatment were also included in the quiescent phase group. Another 90 healthy medical check-ups during the same period were selected as the control group. Peripheral venous blood was collected from subjects in each group, and serum IL-9, YKL-40, and IL-31 levels were compared, and the value of serum IL-9, YKL-40, and IL-31 levels in the diagnosis of CSU was evaluated by using subject operating characteristic curve analysis. Results Serum IL-9 levels ［(139.57±19.68), (104.38±16.35), (102.41±15.64) pg/mL］, YKL-40 levels ［(994.74±87.67), (652.53±62.44), (634.27±59.36) pg/mL］, and IL-31 levels ［(22.39±4.27), (8.13±1.21), (7.88±1.14) pg/mL］ had statistically significant differences among the observation group, stationary period group, and control group (F=115.082, 627.596, 660.505, all P<0.001). Serum IL-9 levels ［(113.54±15.64), (132.62±16.32), (155.35±23.66) pg/mL］, YKL-40 levels ［(757.21±77.67), (884.52±81.64), (1106.67±96.68) pg /mL］, IL-31 levels ［(14.84±2.86), (19.67±3.33), (25.58±4.24) pg/mL］ were statistically significant when compared between the groups (F=27.691, 99.880, 51.110, P<0.001), with all of them being lower in the mild group than in the moderate group and the severe group, and in the moderate group than in the severe group (all P <0.05). There was a significant positive correlation between serum IL-9, YKL-40, and IL-31 levels and UAS7 scores in patients with active CSU (r=0.550, 0.756, 0.699, P<0.01). The ROC curves showed that the AUCs for serum IL-9, YKL-40, and IL-31 were 0.643, 0.686, and 0.735, respectively, and the AUC for the combined assay was 0.842.Conclusion Serum IL-9, YKL-40, and IL-31 levels in patients with active CSU are all significantly elevated with the aggravation of the disease, and thus recovery from CSU is facilitated by regulating IL-9, YKL-40, and IL-31 expression