The present study intends to formulate, characterize and appraise the phospholipid-based nanovesicular system for enhanced delivery of Hesperetin (HT). The quality by design (QbD) approach was employed to prepare Hesperetin naturosomes (HTN) using the solvent evaporation technique and assessed for physicochemical and pharmacological attributes. The FTIR, DSC, and PXRD studies confirmed the successful formation of a vesicular drug-phospholipid complex, while photomicroscopy, SEM, and TEM analysis revealed the morphology of HTN. The functional attributes substantially enhanced the HT’s aqueous solubility, drug release, and membrane permeation. The aqueous solubility of HTN was ~10-fold more than that of pure HT. Likewise, the in-vitro dissolution data of HTN showed better competence in releasing the HT (>93%) than the pure HT (~64%) or the physical mixture (~74%). Furthermore, HTN significantly altered HT permeation (>53%) when compared to pure HT (23%) or the physical mixture (28%). The current study showed that naturosomes are a promising way to improve the solubility in water, bioavailability, and therapeutic effectiveness of drugs.