Polymer-lipid hybrid nanoparticles, PMONPs, were developed to improve the oral absorption of cabazitaxel (CTX), a semi-synthetic taxane derivative, by overcoming multiple gastrointestinal barriers. The nano-carrier is comprised of a poly(ε-caprolactone) (PCL) and chain triglyceride (MCT) hybrid core for drug loading, and a positively charged surface while slightly concealed with a polyethylene oxide (PEO) shell by insertion of poloxamer 188, with the aim of improving the intestinal mucus permeation and epithelial cell uptake. The CTX-loaded PMONPs (CTX-PMONPs) were optimized with 10% MCT content in the core, and characterization showed they were on the nanoscale with a size of 170.2 ± 5.7 nm, zeta potential of + 40.90 ± 3.05 mV, drug loading of 11.5%, and sustained release property. Enhanced mucus permeation of PMONPs were confirmed in a bulk permeation test, in situ SPIP and intestinal distribution study, and is likely attributed to the combined effect of positive charge and hydrophilic PEO layer on the surface. Meanwhile, promoted cellular uptake was found in mucus-secreting cells evaluation, in which potential adsorptive transcytosis, caused by positively charged surface, played a key role. Furthermore, lymphatic transport was positively demonstrated, contributing to the high oral absorption of CTX-PMONPs. The oral bioavailability of CTX was elevated from 7.7% (CTX solution (CTX-Sol)) to 56.6% after oral administration of CTX-PMONPs, approximately 7.3 times higher than that of CTX-Sol. An in vivo anticancer efficiency study showed that CTX-PMONPs orally exhibited a good tumor inhibition effect, and reduced the CTX-caused systemic toxicity compared with intravenous CTX-Sol. In conclusion, PMONPs are able to efficiently orally deliver the anticancer drug, CTX, into systemic circulation, and can achieve the desired oral anticancer effect. This surface modified polymer-lipid hybrid nanoparticle is likely to be a promising carrier for oral delivery of small molecule anticancer drugs.