Xerostomia is a common complaint of nearly half of the elderly population and about one‑fifth of younger adults. It causes several signs and symptoms, and compromise oral functions and health‑related quality‑of‑life. Multiple reasons are proposed to describe the etiology of xerostomia such as local factors, psychogenic factors, and systemic diseases. In order to manage xerostomia effectively, identification of the main causality is mandatory. The aim of this review was to present systemic diseases leading to xerostomia with their mechanisms of action. We used various general search engines and specialized databases such as Google, Google Scholar, Yahoo, PubMed, PubMed Central, MedLine Plus, Medknow, EBSCO, ScienceDirect, Scopus, WebMD, EMBASE, and authorized textbooks to find relevant topics by means of Medical Subject Headings keywords such as “xerostomia,” “hyposalivations,” “mouth dryness,” “disease,” and “systemic.” We appraised 97 English‑language articles published over the last 40 years in both medical and dental journals including reviews, meta‑analysis, original papers, and case reports. Upon compilation of relevant data, it was concluded that autoimmune diseases most frequently involve salivary glands and cause xerostomia followed by diabetes mellitus, renal failure, and graft‑versus‑host disease. Moreover, the underlying mechanisms of systemic disease‑related xerostomia are: autoimmunity, infiltration of immunocompetent cells, granuloma formation, fibrosis and dehydration, deposition of proteinaceous substances, bacterial infection, and side‑effects of medications.