In the present study, the emulsification-diffusion method was optimized in order to obtain omapatrilat/monolein-nanoparticles (omapatrilat/MO-nanoparticles). The antihypertensive effect of omapatrilat/MO-nanoparticles in spontaneously hypertensive rats (SHR) after oral administration was evaluated. The results indicated that the variables involved in the process did not have an influence on particle size, and that the former is directly determined by the amphiphilic properties of MO. When SHR were orally treated with omapatrilat/MO-nanoparticles, blood pressure was significantly reduced and completely normalized after three days. This effect was markedly higher than that observed with omapatrilat suspensions. The effect of omapatrilat/MO-nanoparticles can be attributed to: (i) The molecular dispersion of the drug into the lipophilic domain of monolein's bicontinuous phase; (ii) the adhesive properties of the nanodispersion on the gastrointestinal mucosa; (iii) the high surface area of the dispersion; (iv) the intraluminal interaction between MO, the mixed micelles arising from the digestive process, and omapatrilat; and (v) the well-known absorption-promoting properties of lipids, and in particular, of MO. MO-nanoparticles can be an interesting system to increase the oral bioavailability of drugs.