ABSTRACT Background Chronic spontaneous urticaria (CSU) is a mast cell‐driven disease associated with systemic inflammation and altered immune responses. Haptoglobin (HP), an acute‐phase glycoprotein, exhibits antioxidative and immunomodulatory properties, while zonulin, the precursor of HP‐2, regulates epithelial barrier integrity. We investigated the clinical relevance of serum HP and zonulin in CSU and their association with treatment outcomes. Methods Serum HP and zonulin levels were measured by ELISA in 124 CSU patients and 57 healthy controls (HCs). In 62 CSU patients, follow‐up samples were obtained after 3 months of treatment. Clinical outcomes included the urticaria activity score over 7 days (UAS7) and the urticaria control test (UCT). Results Serum HP levels were significantly higher in CSU patients than in HCs (median 1145.1 vs. 839.2 μg/mL, p < 0.001), whereas zonulin levels did not differ. HP correlated positively, but weakly, with the white blood cell count, C3 and C‐reactive protein (all rho ≈ 0.2), and negatively with disease duration and eosinophil percentage. Zonulin correlated negatively with UCT scores but not with HP. After treatment, HP decreased significantly ( p < 0.001), with greater reductions in patients showing a ≥ 12‐point improvement on the UAS7. Baseline HP was higher in patients who achieved complete control (UCT = 16) than others ( p = 0.017). ROC analysis identified baseline HP ≥ 1249 μg/mL as an optimal cutoff, confirmed as an independent predictor of complete control (odds ratio = 4.23, p = 0.029). Conclusion Serum HP is elevated in CSU patients, decreases with treatment, and independently predicts complete urticaria control. HP may serve as a potentially prognostic biomarker for CSU.