<p>Non-celiac wheat sensitivity (NCWS) is a clinical entity characterized by gastrointestinal and extraintestinal symptoms triggered by wheat ingestion, distinct from celiac disease and wheat allergy. Its pathophysiology is complex and multifactorial, involving alterations in intestinal barrier integrity, gut microbiota dysbiosis, activation of innate and adaptive immune responses, and neuroimmune interactions. These alterations, however, are not specific to NCWS and may also be observed in other conditions. Emerging evidence highlights the role of non-gluten wheat components, gut dysbiosis, and neuro-immune interactions exacerbating immune responses and visceral hypersensitivity. Clinically, NCWS patients present with a wide spectrum of gastrointestinal symptoms and extraintestinal manifestations including fatigue and neuropsychiatric disorders, underscoring the need for a multidisciplinary approach. Diagnosis remains challenging due to the absence of validated biomarkers. It is predominantly based on the exclusion of celiac disease and wheat allergy, symptom resolution upon wheat withdrawal, and symptom recurrence after blinded wheat exposure, as recommended by the Salerno Experts’ Criteria. Current management primarily involves dietary interventions, such as gluten-free or wheat-free diets, often complemented by low-FODMAP diets and strategies targeting microbiome modulation. However, restrictive diets may lead to nutritional deficiencies and impact quality of life, highlighting the necessity for personalized dietary interventions. This comprehensive review synthesizes recent advances in understanding the pathophysiology of NCWS, emphasizing their clinical implications for diagnosis and management, and identifies critical areas for future research.</p>