The present study aims to develop cubosomes with surface cross-linked chitosan for sustained drug delivery and enhanced oral bioavailability of vinpocetine (VPT). GMO based liquid cubosomes with VPT loading were prepared by the high pressure homogenization method. In order to enhance the anti-digestion effect, chitosan was cross-linked on cubosomes by the Schiff reaction, followed by solidification spray drying. The obtained spray-dried cubosomes (chito-cubosomes) are spherical microspheres with nano-sized holes on the surface. After reconstitution, the particle size and zeta potential of chito-cubosomes were determined to be ∼250 nm and +35.9 mV, respectively. In comparison to unmodified liquid cubosomes, chito-cubosomes exhibited a significant anti-digestion effect with a typical sustained release profile. In comparison to a VPT suspension, liquid cubosomes showed a 2.5-fold higher and 3.0-fold higher AUC, while chito-cubosomes further enhanced bioavailability (5.0-fold) with prolonged MRT (2.2-fold) and delayed (2.8-fold). The results suggested that chito-cubosomes could be a promising drug carrier for enhancing oral absorption with sustained release behavior.