Carvedilol (CARV) -a nonselective β-receptor antagonist indicated in treatment of hypertension-suffers from poor oral bioavailability due to its poor solubility and hepatic first-pass metabolism. This study aimed to optimize CARV-loaded cubosomes to enhance oral CARV bioavailability and prolong its action in the treatment of hypertension. D-optimal design was used to optimize CARV CUBs based on either Polyvinyl alcohol (PVA) or Cremophor RH 40 (RH 40) as secondary stabilizers. Furthermore, the effect of Poloxamer P407 percentage and secondary stabilizer concentration was studied. Comparing PVA-based to the RH 40-based CUBs, CARV-CUBs-RH40 showed lower particle size (PS), higher polydispersity index (PDI), lower zeta potential (ZP) and slightly lower CARV content. Optimized PVA-based and RH 40-based CUBs showed PS of 141 ± 1 nm and 105 ± 0 nm, PDI of 0.166 ± 0.00 and 0.247 ± 0.01, ZP of 4.9 ± 0.3 mV and 6.3 ± 0.3 and CARV content of 105.0 ± 1.4 % and 93.6 ± 0.9 %, respectively. TEM imaging confirmed the characteristic cubic morphology of the prepared CUBs. Moreover, the prepared CARV-CUBs exhibited an in vitro sustained release behavior and comparable in vivo antihypertensive performance.