Itraconazole, a triazole antifungal agent, is pivotal in treating invasive fungal infections, yet its erratic absorption and poor bioavailability present therapeutic challenges. Conventional itraconazole formulations often result in variable pharmacokinetics, yielding suboptimal outcomes. Addressing these limitations, Super Bioavailable (SUBA) itraconazole was developed, aiming for improved solubility and absorption. This study investigates the pharmacokinetic and bioequivalence profiles of SUBA itraconazole against conventional formulations in healthy volunteers. A randomized, three-arm, three-period study was conducted under fed conditions. Plasma concentrations of itraconazole and its active metabolite hydroxyitraconazole were quantified using LC-MS/MS, employing a validated bioanalytical method per US FDA guidelines. Additionally, in vitro skin deposition assays and cardiac safety evaluations were performed. The developed bioanalytical method demonstrated accuracy, reproducibility, and stability. SUBA itraconazole exhibited enhanced pharmacokinetic parameters and bioavailability compared to conventional formulations. In vitro skin deposition assays revealed optimal drug availability in the stratum corneum. Notably, SUBA itraconazole demonstrated superior cardiac safety profiles, evident from QT interval assessments. The study provides precise pharmacokinetic data supporting the bioequivalence of SUBA itraconazole with conventional formulations. Skin deposition studies elucidate drug distribution within skin layers, while cardiac safety evaluations underscore its favorable profile, potentially mitigating cardiac risks associated with therapy. These findings underscore the efficacy and safety advantages of SUBA itraconazole, highlighting its clinical utility in antifungal therapy.