Aim The present study endeavours to develop a solid self-microemulsifying nutraceutical drug delivery system for hesperidin (HES) using quality by design (QbD) to improve its biopharmaceutical attributes. Methods A 3(2) full factorial design was employed to study the influence of factors on selected responses. Risk assessment was performed by portraying Ishikawa fishbone diagram and failure mode effect analysis (FMEA). The in vivo antidiabetic study was carried on induced diabetic rats. Results The optimised liquid SMEDDS-HES (OF) formulation showed emulsification time (Y (1)) = 102.5 +/- 2.52 s, globule size (Y (2)) = 225.2 +/- 3.40 nm, polydispersity index (Y (3)) = 0.294 +/- 0.62, and zeta potential (Y (4)) = -25.4 +/- 1.74 mV, respectively. The solid SMEDDS-HES (SOF-7) formulation was characterised by FTIR, PXRD, DSC, and SEM. The shelf life of SOF-7 was found to be 32.88 months. The heamatological and histopathological data of diabetic rats showed prominent antidiabetic activity. Conclusions The optimised formulation showed improved dissolution, desired stability, and promising antidiabetic activity.