Introduction: Chronic spontaneous urticaria (CSU) is an inflammatory skin disease of a not known cause characterized by hives, itching and possible associated angioedema, lasting for at least 6 weeks. Subjects and Methods: This prospective study included 41 patients with CSU. Values for salivary IL-6, amylase (control) and serum CSU biomarkers (IL-6, KKS, ESR, CRP, TSH, T3, T4, anti-TPO, anti-TG, D-dimers and vitamin D) were measured and compared with CSU activity as measured by the Urticaria Activity Score (once-daily UAS and UAS7), CSU control as measured by the Urticaria Control Test (UCT), and patients’ quality of life as measured by the Dermatology Life Quality Index (DLQI) and Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL). Patients were prospectively monitored and treated with antihistamines for 3 months. Saliva and blood samples were taken, and the questionnaires were filled out and evaluated, at an initial timepoint (T1) and control (T2) follow-up time. Results: Although serum and salivary IL-6 values did not correlate with CSU severity, slightly higher serum IL-6 values were observed in patients with more severe forms of the disease. Higher salivary IL-6 values were observed in patients with mild CSU, although without statistical significance. Serum IL-6 values statistically significantly correlated with CRP, ESR, D-dimers, T3 and T4 (p < 0.001), while salivary IL-6 values were only statistically significantly correlated with CRP (p = 0.044). Basophil concentration statistically significantly correlated with CSU severity (once-daily UAS, p = 0.017). ESR values were a statistically significant predictor of CSU activity (UAS7, p = 0.038), and T4 values had a statistically significant negative correlation with CSU duration (p = 0.036). At the 3-month follow-up timepoint, CSU activity (once-daily UAS and UAS7) had significantly decreased (p = 0.014 and p = 0.015), while quality of life (DLQI) and CSU control (UCT) had significantly increased (p = 0.006 and p = 0.005). Conclusion: Higher serum IL-6, basopenia and higher ESR were observed in more severe and poorly controlled cases of CSU, while poorer patient quality of life and higher T4 values were seen in CSU cases of longer duration. Standard CSU treatment reduced disease activity and increased disease control and patient’s quality of life. The serum and salivary parameters mentioned above could potentially be reliable biomarkers and indicators of CSU during treatment and follow-up.