Background and Purpose: Thrombolytic therapy has remained utterly challenging in hyperglycemic patients for poor prognosis and increased hemorrhagic conversions. We have recently shown that tissue plasminogen activator (tPA)-induced cerebrovascular damage is associated with thioredoxin interacting protein (TXNIP) upregulation, which has an established role in the detrimental effects of hyperglycemia. In the present work, we investigated whether verapamil, as an established TXNIP inhibitor may provide protection against hyperglycemic stroke and tPA-induced blood-brain barrier (BBB) disruption. Experimental approach: Acute hyperglycemia was induced by intraperitoneal administration of 20% glucose 15 min prior to transient middle cerebral artery occlusion (tMCAO). Verapamil (0.15 mg/kg) or saline was intravenously infused with tPA at hyperglycemic reperfusion, 1 h post tMCAO. After 24 h of ischemia/reperfusion (I/R), mice were tested for neurobehavioral deficits followed by evaluation of infarct size, edema, and microbleeding. Alterations in TXNIP, inflammatory mediators, and BBB markers were further analyzed using immunoblotting or immunostaining techniques. Key results: As an adjunctive therapy, verapamil significantly reduced tPA-induced BBB leakage, matrix metallopeptidase 9 (MMP-9), and tight junction protein deregulation, all leading to less hemorrhagic conversions. Importantly, verapamil strongly reversed tPA-induced TXNIP/NRRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation, along with reduced infarct area. This concurred with a remarkable decrease in high mobility group box protein 1 (HMGB-1)/ nuclear factor kappa B (NF-κB) stimulation leading to less priming of NLRP3 inflammasome. Conclusion and implication: This preclinical evidence supporting verapamil as a safe adjunctive therapy in thrombolytic approaches, underlines TXNIP’s detrimental role in BBB disruption in metabolic distress.