Systemic lupus erythematosus is a multisystemic autoimmune disease, with the presence of autoantibodies towards nuclear antigens, immune complex deposition, and chronic inflammation that typically occurs in the skin, joints, and kidneys. Clinical manifestation of systemic lupus erythematosus varies significantly, and the oral mucosa can also be affected. Oral manifestations of this disorder are also highly variable, ranging from unspecific ulcerations to bullae, erythematous erosions, and whitish striated lesions more often affecting the palate, followed by the lips, buccal mucosa, gingiva and tongue. Clinical differential diagnosis of oral manifestations of systemic lupus erythematosus includes many other autoimmune disorders and demands a strict clinical, laboratory and microscopic study preferentially under a multidisciplinary evaluation. Microscopic findings reveal a dense inflammatory infiltrate predominantly composed of lymphocytes that should be differentiated from neoplastic conditions. The use of hydroxychloroquine isolated or in combination with steroids or other immunomodulatory drugs often leads to disease control, but the disease activity and comorbidities developed due to the side effects of therapy negatively impact patients’ quality of life and prognosis. Oral hyperpigmentation of the palate during chronic use of hydroxychloroquine is a well-known and reversible side effect of the therapy, which, however, may also be associated with serious ocular complications.