Sodium nitroprusside is used especially in intensive care units (ICUs) to treat malignant hypertension. However, its clinical application is often limited by the release of cytotoxic cyanide. This study aimed to evaluate the pharmacological safety of a sodium nitroprusside formulation incorporated into amine-functionalized mesoporous silica nanoparticles. Systemic hemodynamic studies and mesenteric bed reactivity assays were conducted in male normotensive Wistar-Kyoto rats and Spontaneously Hypertensive Rats. Animals were treated with mesosporous nitroprusside formulation (0.1, 1, and 3 mg/kg, i.v.) compared to sodium nitroprusside at the same doses. Mesosporous nitroprusside formulation and sodium nitroprusside had comparable antihypertensive potential, with significant dose-dependent reductions in blood pressure and peripheral resistance. Additionally, the mesosporous nitroprusside formulation effectively relaxed resistance arteries of the mesenteric bed to a similar magnitude as SNP. Moreover, while the mesosporous nitroprusside formulation preserved baroreflex function, sodium nitroprusside at the same dose impaired it. Furthermore, the QTc interval remained unaltered following the mesosporous nitroprusside formulation administration, whereas sodium nitroprusside increased the QTc interval. In addition, free sodium nitroprusside, induced respiratory distress which was not observed in the mesosporous nitroprusside formulation. The silica nanoparticle MPSi-NP exhibited the same pharmacological profile of SNP associated to a better safety profile.