Paclitaxel (PTX) is widely used in the clinical treatment of cancer, and peripheral neuropathy is a common adverse side effect of PTX. Diverse mechanisms contribute to the development and maintenance of PTX-induced peripheral neuropathy. However, the role of the spinal Notch pathway in PTX-induced peripheral neuropathy is not completely understood. A Sprague-Dawley male rat model of PTX-induced peripheral neuropathy was established by nab-PTX. A total 120 rats were randomly divided into a control group ( = 36), PTX d8 group ( = 6), PTX d15 group (PTX group,  = 36), PTX d21 group ( = 6), and PTX+N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) (Notch pathway inhibitor) group ( = 36). The expression of Notch downstream signaling molecules, including NICD, JAG1, and Hes1 was examined in the control group, PTX d8 group, PTX d15 group, and PTX d21 group. The effects of the DAPT on behavioral assays, apoptosis, neuronal and axonal injury, glial responses, and vascular permeability were detected. The monolayer of mouse brain microvascular endothelial cells was used to simulate vascular permeability in vitro. Cells were divided into the following groups: control group, nab-PTX group, PTX+DAPT group, PTX+DAPT+recombinant mouse high mobility group Box 1 (rmHMGB1) group, and PTX+rmHMGB1+methyl--cyclodextrin (MCD) group. The underlying mechanisms were explored by examining the expression and translocation of the HMGB1/caveolin-1 signaling pathways, inflammatory cytokines, and oxidative stress in vivo and in vitro. The levels of Notch downstream signaling molecules were elevated and peaked at d15 after nab-PTX treatment. The mechanical and thermal pain thresholds of rats were decreased with nab-PTX treatment, accompanied by enhanced apoptosis, neuronal and axonal injury, glial responses, and vascular permeability. DAPT could restore the mechanical and thermal thresholds and decrease apoptosis, neuronal and axonal injury, and glial responses induced by nab-PTX. DAPT also protected vascular permeability by increasing the expression of tight junction proteins in vivo. RmHMGB1 could abrogate the protective effect of DAPT on vascular permeability, while the inhibitor of caveolin-1, MCD, could further abrogate the effect of rmHMGB1 in vitro. DAPT relieved nab-PTX-induced peripheral neuropathy by inhibiting the activation of the HMGB1/caveolin-1 signaling pathways and decreasing the levels of inflammatory cytokines and oxidative stress in vivo and in vitro. Taken together, the results of this study demonstrated that the Notch pathway may serve as a potential target for PTX-induced peripheral neuropathy intervention.