Low aqueous solubility and intestinal permeability limit the oral chemotherapy efficacy of paclitaxel (PTX). Traditional nanodrug delivery systems show excellent aqueous solubility improved ability of PTX. However, gastrointestinal (GI) mucus limits the improvement of intestinal permeability in traditional nanodrug delivery systems. A novel mucus adhesion- and penetration-functionalized chitosan-thioglycolic acid-Pluronic F127 (CS-TGA-PF) liposome system was developed for PTX oral delivery. The optimized formulation of PTX-loaded CS-TGA-PF liposomes showed particle size of 121.4 nm and zeta potential of 50.2 mV. CS-TGA-PF liposomes were more stable than unmodified liposomes and demonstrated a sustained-release manner of PTX incubated in simulated gastric fluid and intestinal fluid. CS-TGA-PF liposomes absorbed a three-fold amount of mucin compared with that of unmodified liposomes, which would prolong the residence time of liposomes on the mucosal surface in the intestinal tract. The intestinal mucus adhesion- and penetration-enhanced efficacy of CS-TGA-PF liposomes for intestinal PTX delivery was studied by observing the intestinal absorption and distribution. Results exhibited increased liposome uptake by the GI mucosa and improved drug intestinal absorption. In conclusion, the dual functional CS-TGA-PF liposomes with mucus adhesion- and permeation-enhanced properties could be used as a promising nanodrug delivery system for PTX oral delivery.