Background/Objectives: Histamine intolerance is becoming a critical medical problem across numerous clinical specialties, due to the absence of a standardized diagnostic and therapeutic strategy to manage patients with a suspicion of or diagnosis of this condition. Histamine intolerance is a type of non-immune food hypersensitivity, characterized by heterogenous etiologies and a very broad range of symptoms. The condition is the result of an imbalance between the amount of histamine accumulated within the body and the body’s systemic ability to degrade it. In regard to the diagnostics of histamine intolerance, the need to preliminarily exclude other potential conditions associated with increased histamine levels in the blood has been highlighted. The co-occurrence of allergies and histamine intolerance is not uncommon, and the similarity of the clinical manifestations can lead to diagnostic, as well as therapeutic, difficulties. This paper details the diagnostic and clinical workflow for a patient with histamine intolerance and polyvalent allergy comorbidity, with the aim being to help outline a protocol that may be helpful to clinicians managing patients with histamine intolerance. Case Presentation: This article presents the case of a 30-year-old patient with a polyvalent allergy and multimorbidity (allergic rhinitis, asthma, a food allergy, and eosinophilic esophagitis), with comorbid histamine intolerance. Due to the violent and severe symptoms, including facial erythema, urticaria, pruritus, abdominal pain, and tachycardia, experienced after meals, the patient received intramuscular epinephrine injections three times a week. The diagnostic protocol and the course of therapeutic management are presented. Conclusions: The diagnosis of histamine intolerance is difficult due to the high variability and heterogeneity of clinical symptoms in individual patients. Many studies on the issue recommend ruling out an allergic background in terms of the complaint. However, the possibility of the symptoms of an IgE-dependent allergy overlapping with those of histamine intolerance should be taken into account in every case. This is particularly important in patients presenting with an atypical and severe course of allergic diseases. The clinical case presented herein may be helpful for the daily practice of allergologists and physicians with other specialties, as an example of multimorbidity with both allergic and non-allergic backgrounds.