Strokes are a major cause of disability in systemic lupus erythematosus (SLE). Classical neurological manifestations are rare at onset. The use of thrombolytic therapy improves clinical outcome in eligible stroke patients who present early. Modern imaging modalities augment decision making. This 37-year-old woman presented with an acute stroke with National Institute of Health stroke scale 10. The CT showed a hyperdense middle cerebral artery (MCA) dot sign. The magnetic resonance angiography revealed focal thromboembolic occlusion at the insular MCA segment (M2). Intravenous recombinant tissue plasminogen activator (rtPA) was administered with successful recanalization. The present case was a rare event for rtPA use in acute MCA occlusion with underlying latent lupus. Acute vascular event thrombolysis as the presenting manifestation of autoimmune disease has not previously been encountered on literature review. Stroke pathophysiology in conditions of hypercoagulability is a significant clinical entity where the implication for thrombolytic use requires further studies. An ischemic stroke with underlying connective tissue disease benefits from timely multimodal brain imaging and should be considered for reperfusion.