Systemic lupus erythematosus (SLE) is a multisystem connective tissue disorder that also affects all the components of the neurological system, such as autonomic, peripheral, and central nervous systems. There was no link between autonomic dysfunction and lupus activity or the presence of peripheral neuropathy. Anhidrosis and hypohidrosis are most usually caused by local skin injury (e.g., related to trauma, radiation, infection [e.g., leprosy], or inflammation) or gland atrophy caused by connective tissue illness (e.g., systemic sclerosis, systemic lupus erythematosus, and Sjögren syndrome). Drugs, particularly those with anticholinergic effects, can possibly induce it. Diabetic neuropathy, thyroid problems, and other factors might potentially contribute to it. Here is a rare case report of patchy segmental anhidrosis with compensatory hyperhidrosis as the presenting manifestation of SLE treated with topical sunscreen, topical glycopyrrolate, and oral hydroxychloroquine with mild clinical improvement. However, anhidrosis showed no improvement.