BACKGROUND: Xuanshen decoction (XSD) is a traditional Chinese medicine formulation that is often applied in treating slow transit constipation (STC). However, its specific therapeutic mechanism remains to be characterized. AIM: To investigate the mechanism of XSD for STC, we combined network pharmacology prediction, molecular docking analysis, and studies. METHODS: The therapeutic effects of XSD on loperamide-induced STC in rats were assessed through 24-hour fecal number, fecal moisture content, and intestinal propelling rate. Hematoxylin-eosin and Alcian blue/periodic acid-Schiff staining were applied to analyze colonic mucosa for histopathological presentation and mucin production. Next, the mechanism of action of XSD for STC was elucidated through network pharmacology and molecular docking analyses, and the findings were validated by the animal experiments. RESULTS: XSD significantly alleviated the symptoms of STC in rats. Relative to the STC rats, in the medium-dose XSD and high-dose XSD rats, stem cell factor, C-kit, phospho-phosphoinositide 3-kinase/phosphoinositide 3-kinase, phospho-protein kinase B/protein kinase B, catalase, and superoxide dismutase were substantially upregulated ( < 0.01); nuclear factor erythroid 2-related factor 2 (nuclear/cytoplasmic) and B-cell lymphoma 2 (Bcl-2) were increased ( < 0.05), while cleaved caspase-3, Bcl-2-associated X protein (Bax)/Bcl-2, and malondialdehyde were significantly reduced ( < 0.01). Heme oxygenase-1 and glutathione peroxidase in the high-dose XSD group were significantly increased ( < 0.01), and Bax was statistically lowered ( < 0.01); glutathione peroxidase in the medium-dose XSD group was increased ( < 0.05), while Bax was reduced ( < 0.05). CONCLUSION: XSD may inhibit oxidative-stress-induced apoptosis in interstitial cells of Cajal by stimulating the phosphoinositide 3-kinase/protein kinase B/nuclear factor erythroid 2-related factor 2 pathway, thereby effectively treating STC.