The present investigation sought to elaborate upon the conceptualization and evaluation of buoyant microspheres through the emulsion solvent diffusion method, employing Eudragit RS 100 and Eudragit RL 100. A groundbreaking solid dispersion of Hydrochlorothiazide-Losartan potassium was recently unearthed to amplify the aqueous solubility of Hydrochlorothiazide, an inherently insoluble pharmacotherapeutic agent, consequently ameliorating its pharmacodynamic manifestations. Prior endeavors to address the solubility quagmire of Hydrochlorothiazide have traversed an array of methodologies, and this inquiry directed its focus towards the formulation and meticulous assessment of floating microspheres. The fabricated microspheres underwent an exhaustive array of analyses, encompassing the dimensions of particle size, percentage entrapment efficiency, drug encapsulation efficiency (DEE), Fourier-transform infrared (FTIR) spectroscopy, in vitro release kinetics, and stability evaluations. The particle size distribution values of 112±0.02 and 160±0.04 µm, presenting themselves as alabaster-hued, unencumbered, and approaching nearspherical geometry. FTIR examination showed an absence of discernible interaction between the therapeutic agent and the polymeric matrix. The developed Floating Microspheres with Losartan Potassium and Hydrochlorothiazide, specifically the F5 formulation, exhibited remarkably propitious and protracted drug release profiles, persisting up to the 24th temporal hour. This sustained therapeutic efflux is prognosticated to engender heightened patient adherence and augment bioavailability, proffering a more efficacious modality for the management of hypertensive pathophysiology. Moreover, the anticipated angiotensin receptor antagonism imparted by Losartan is poised to attenuate the proclivity for enduring complications associated with hypertensive maladies, thereby mitigating the hazards of cardiac insufficiency, congestive heart failure (CHF), myocardial infarction, and vasculopathic detriment to blood vessels and renal parenchyma.