Nanoemulsions of eplerenone (EP) were designed with the aim of improving its bioavailability for an effective antihypertensive therapy. Nanoemulsions were prepared by high shear homogenization and ultrasonication methods. Oleyl erucate, Brij (R) 35, Tween (R) 80, Tego Care (R) 450 and Poloxamer (R) 407 were used as the liquid lipid and surfactants for optimization of formulations by design of experiments approach. Thus, oil, surfactant and water contents of nanoemulsions were defined by determination of their droplet size and droplet size distribution by dynamic light scattering method. Formulations were screened by scanning electron microscopy. Drug payload and release properties of the formulations were investigated. Analytical quantification method of EP was validated by high performance liquid chromatograpy. Nanoemulsions having average droplet size between 150.6 nm and 205.8 nm were gained with homogenous droplet size distribution and high entrapment efficiency (84.47-98.51%). Formulations released 44.37-82.87% of EP within 1 h and drug release was completed up to 5-6 h. Thus, drug release characteristics of formulations optimized in this study might introduce benefits for rapid response and maintenance of treatment in hypertension attacks. As a result, design of experiments approach provided accurate and consistent datum with those obtained from experiments on the bench for optimization of formulations.