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The oral absorption of paclitaxel (PTX) is restricted by poor solubility in the gastrointestinal tract (GIT), low permeability, and high first-pass metabolism. Lipid carriers, such as a self-microemulsifying drug delivery system (SMEDDS), have been deemed as promising vehicles for promoting oral delivery of PTX. Herein, a lipophilic disulfide-bridged linoleic prodrug (PTX-S-S-LA) was synthesized and efficiently incorporated into SMEDDS to facilitate the oral absorption of PTX. This study mainly aims to evaluate the usefulness of the disulfide-bridged linoleic prodrug incorporated with SMEDDS and provides a new strategy for efficient oral delivery of PTX. The prodrug SMEDDS showed a markedly higher drug loading efficiency (3fold) compared to that of parent PTX. PTX-S-S-LA SMEDDS significantly increased the drug partition (about 1.9-fold) in the intestinal micellar aqueous phase compared to PTX in the in vitro lipolysis study. Additionally, the gastrointestinal (GI) biodistribution study demonstrated that SMEDDS could enhance the GI biological adhesion and go through the lymphatic system to transport. Moreover, it was found that the reduction-sensitive prodrug (PTX-S-S-LA) has good stability in the GIT, leading to an improved antitumor efficiency without significant GI toxicity. Overall, the PTXlinoleic prodrug (PTX-S-S-LA) in combination with SMEDDS provides a promising way to enable effective oral delivery of PTX.