Urticaria is a condition characterized by the development of itchy wheals (hives), angioedema, or both. The pathophysiology of chronic spontaneous urticaria (CSU) is still poorly understood. It is suggested that there is no dominant and independent mechanism of CSU; however, there are different immunological and non-immunological abnormalities that act simultaneously or/and follow each other resulting in clinical symptoms. The latest hypothesis points out that mast cells (MCs) to be activated via autoantibodies in autoallergic or autoimmune mechanism mediators released from degranulated MCs are responsible for the vasoactive and neurospecific effect in CSU. According to many clinical observations, it is suggested that psychological stress can be both a triggering factor in the onset of CSU and a modulating one in the course of the disease and therapy effectiveness. Of importance, the mechanistic background of the psychological stress response in the skin has not yet been fully elucidated. However, of note, a variety of inflammatory mediators, neuropeptides, and neurotransmitters facilitate this phenomenon. This review presents recent findings on the neuro–immuno–psychological aspects of CSU, highlighting an emerging role of neuro–immune interactions. It also points out the usefulness of psychological tools employment for the baseline diagnosis of perceived stress level and the presence of its symptoms. Furthermore, it proposes the implementation of non-invasive interventions to reduce psychological stress and anxiety. A bio–psycho–social approach including psychological support and patient education seems to be as important as traditional pharmacotherapy for CSU. It facilitates the effective control of active disease and a prolonged remission time in this disease.