Background: Patients with chronic urticaria (CU) often report an impaired quality of life (QoL). Although a positive effect of addressing spirituality in health care has been proved in several chronic diseases, its potential role in CU has received no attention. This study evaluated spirituality and QoL in CU subjects with different control levels. Methods: In a single-centre observational study, 100 CU subjects were investigated using Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-Sp-12) scale, Chronic Urticaria Quality of life Questionnaire (CU-Q2oL) and Urticaria Control Test (UCT). Results: Of 100 subjects, 82 were female and 18 were male. It was observed that subjects with not controlled CU presented FACIT Sp-12 meaning/peace (p = 0.004) significantly lower, and CU-Q2oL (p <0.0001) significantly higher (worst QoL) than subjects with controlled CU. There was no difference in the FACIT Sp-12 faith (p = 0.43) between groups. There was moderate direct correlation between FACIT Sp-12 faith and FACIT Sp-12 meaning/peace (r = 0.483; p <0.0001; n = 100). There was a significant strong inverse correlation between the CU-Q2oL and the UCT (r = -0.762; p <0.0001; n = 100). No correlation was found between the FACIT Sp-12 faith and CU-Q2oL, neither with UCT. Conclusion: No study has ever investigated the role of spirituality in managing patients with urticaria. Our findings support the impact of poorly controlled urticaria in spiritual well-being and QoL. Therefore, clinicians should pay more attention to spirituality among CU patients. We suggest that urticaria guidelines should include specific recommendations on spirituality assessment.