We report a case of multiphasic disseminated encephalomyelitis (MDEM) associated with systemic lupus erythematosus (SLE) and antiphospholipid syndrome. The initial presentation was suggestive of multiple sclerosis. Further clinical attacks, MRI imaging, and CSF findings led to a diagnosis of disseminated encephalomyelitis (DEM). Multiple episodes of neurological dysfunction, which differed in clinical presentation, further categorized the diagnosis as multiphasic DEM. The co-occurrence SLE and antiphospholipid syndrome is unusual and provided an additional diagnostic challenge.