Abstract: Objective To investigate the levels of Mas-related G protein-coupled receptor member X2 (MRGPRX2), interleukin (IL)-6, and IL-24 in the serum of patients with chronic spontaneous uticaria (CSU) and their significance in the pathogenesis of the disease. Methods A total of 75 CSU patients who were admitted to the Affiliated Hospital of Xuzhou Medical University between September 2023 and December 2023 were enrolled as a case group. According to disease severity, they were categorized into three groups: a mild group, a moderate group, and a severe group. The Urticaria Activity Score (UAS7) and Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) scores were evaluated. Additionally, 60 healthy individuals were selected as a control group. The levels of serum MRGPRX2, IL-6, and IL-24 were compared among the groups, and their correlation with UAS7 and CU-Q2oL scores was analyzed. Results The levels of serum MRGPRX2, IL-6, and IL-24 were significantly higher in the case group than those in the control group (P<0.05). Increased levels of serum MRGPRX2 and IL-6 were positively correlated with the severity of CSU (r=0.531, P<0.05; r=0.462, P<0.05), while IL-24 levels did not show a significant correlation with disease severity (r=0.015, P>0.05). Logistic regression analysis indicated that elevated levels of serum MRGPRX2, IL-6, and IL-24 were independent risk factors for the occurrence of CSU (P<0.05). Receiver operating characteristic (ROC) curve analysis demonstrated that the combined prediction model based on MRGPRX2, IL-6, and IL-24 had a higher area under the curve (AUC) than any individual marker alone (P<0.05). Conclusions The levels of serum MRGPRX2, IL-6, and IL-24 are elevated in CSU patients and associated with disease severity. The combined detection of these three biomarkers offers superior diagnostic performance for CSU to individual markers alone.