Scanty solubility and permeability of diosmin (DSN) are perpetrators for its poor oral absorption and high inter-subject variation. This article investigated the potential of novel DSN nanosuspensions to improve drug delivery characteristics. Bottom-up nanoprecipitation technique has been employed for nanosuspension development. Variables optimized encompassed polymeric stabilizer type, DSN: stabilizer ratio, excess stabilizer removal, spray drying, and mannitol incorporation. In vitro characterization included particle size (PS), infrared spectroscopy (IR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), transmission electron microscope (TEM), scanning electron microscopy (SEM), and dissolution profile. Ex vivo permeation was assessed in rats using non-everted sac technique and HPLC. Optimal DSN nanosuspension (DSN:hydroxypropylmethyl cellulose HPMC 2:1) was prepared with acid base neutralization technique. The formula exhibited the lowest PS (336 nm) with 99.9% drug loading and enhanced reconstitution properties after mannitol incorporation. SEM and TEM revealed discrete, oval drug nanocrystals with higher surface coverage with HPMC compared to MC. DSN nanosuspension demonstrated a significant enhancement in DSN dissolution (100% dissolved) compared to crude drug (51%). Permeation studies revealed 89% DSN permeated from the nanosuspension after 120 min compared to non-detected amounts from drug suspension. Conclusively, novel DSN nanosuspension could successful improve its dissolution and permeation characteristics with promising consequences of better drug delivery.