The present study aimed to demonstrate the antiproliferative effect of hyperoside from Zanthoxylum bungeanum leaves (HZL) and explain the underlying molecular mechanisms in the SW620 human colorectal cancer cell line. The cytotoxic effects of HZL were determined using a3‑(4,5‑dimethylthiazol‑2‑yl)2,5‑diphenyltetrazolium bromide assay. Apoptosis and cell cycle were detected using flow cytometry. Reactive oxygen species (ROS) levels and mitochondrial membrane potential (∆Ψm) were assessed using 2',7'‑dichlorofluorescin diacetate and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl carbocyanine iodide fluorescence spectrophotometry, respectively. Western blot analysis was used to quantify the expression levels of apoptosis‑associated proteins. Reverse transcription‑quantitative polymerase chain reaction analysis was used to determine the mRNA expression of glutathione peroxidase (GSH‑Px) and catalase (CAT). HZL had a marked anti‑proliferative effect on the SW620 human colorectal cancer cells by inducing cell cycle G2/M phase arrest and apoptosis, which was associated with an increase in the expression of p53 and p21. Further mechanistic investigations revealed that the induction of apoptosis was associated with increased generation of ROS, reduced ∆Ψm, and upregulation of B‑cell lymphoma 2‑associated X protein, cytochrome c, caspase‑9, apoptotic protease activating factor 1 and caspase‑3. The antitumor potency of HZL was also attributed to inhibition of the mRNA expression levels of GSH‑Px and CAT. These data indicated that HZL may be involved in the pro‑apoptotic signaling of SW620 human colorectal cancer cells via induction of the caspase‑dependent apoptosis and p53 signaling pathways.