Sunitinib (SUNI) is a small-molecule tyrosine kinase inhibitor with limited water solubility, extensive first-pass metabolism, and low oral bioavailability, restricting its therapeutic efficacy. This study aimed to enhance SUNI solubility, sustain its release, and improve oral bioavailability through cubosome-based nanoparticulate delivery. Glyceryl monooleate (GMO) cubosomes were prepared using high-pressure homogenization (HPH) and optimized via a Box-Behnken Design (BBD) to evaluate the effects of formulation and process variables—including GMO/Pluronic F-127 ratio, drug concentration, homogenization pressure, and homogenization cycles on particle size (PS), polydispersity index (PDI), and entrapment efficiency (%EE). Characterization using ATR-FTIR, DSC, XRD, and TEM confirmed the absence of drug-excipient interactions, successful drug incorporation in an amorphous form, and nanostructured morphology. The optimized cubosomes, containing 5.07% w/w lipid, 0.7% w/w stabilizer, 500 MPa homogenization pressure, and 8 cycles, exhibited PS of 77.8 ± 3.43 nm, PDI 0.241 ± 0.004, %EE 71.46 ± 2.01%, and zeta potential − 31.2 ± 2.34 mV. In vitro release studies demonstrated sustained drug release for over 12 hours compared to the pure drug. Pharmacokinetic evaluation in vivo revealed significant enhancement, with C max and AUC₀–∞ increased 3.78- and 5.58-fold, respectively, and oral bioavailability improved 5.6-fold relative to SUNI suspension. These findings suggest that SUNI-cubosomes represent a promising oral drug delivery system, combining enhanced absorption and prolonged release, which may improve the therapeutic performance of sunitinib.