Objective To investigate the effects of safflower polysaccharide on tumor growth and the Phosphoinositide 3?kinase （PI3K）/Protein Kinase B （Akt）/Mammalian Target of Rapamycin （mTOR） signaling pathway in colorectal cancer mice. Methods The mouse model of colorectal cancer was established by inoculating SW480 colorectal cancer cells. The successfully modeled mice were divided into five groups： the control group， the low?dose safflower polysaccharide group 15 mg/（kg·day）， the medium?dose safflower polysaccharide group 45 mg/（kg·day）， and the high?dose safflower polysaccharide group 135 mg/（kg·day）. After treatment， tumor volume， mass， and tumor inhibition rate were measured. Immunohistochemistry was used to detect the expression of Proliferating Cell Nuclear Antigen （PCNA） protein. Apoptosis was assessed using the Terminal deoxynucleotidyl Transferase?Mediated Nick End Labeling （TUNEL） method. Hematoxylin?Eosin （HE） staining was performed to observe the morphology of tumor tissues. Real?time polymerase chain reaction （RT?PCR） was employed to measure the expression levels of PI3K， Akt， and mTOR in tumor tissues from each group. Western blot analysis was conducted to evaluate the expression levels of c?Myc， Bcl?2?associated X protein （Bax）， and proteins related to the PI3K/Akt/mTOR pathway. Results Compared with the model group， the safflower polysaccharide （low， medium， and high） dose groups exhibited significantly decreased tumor mass and volume， as well as reduced mRNA levels of PI3K， Akt， and mTOR. Additionally， the expression ratios of p?PI3K/PI3K， p?Akt/Akt， p?mTOR/mTOR， and c?Myc protein were notably decreased， while the expression of Bax protein was significantly increased （P < 0.05）. As the concentration of safflower polysaccharide increased， the tumor inhibition rate also increased （P < 0.05）. In the model group， tumor tissue from mice showed a higher number of PCNA?positive cells； TUNEL staining revealed minimal green fluorescence， indicating low apoptosis rates. The tumor cells were closely packed， large in size， and poorly differentiated. Conversely， in the different dosage safflower polysaccharide groups， the expression of PCNA in tumor tissues was markedly reduced， and TUNEL staining positive cells （green） were significantly increased， leading to higher apoptosis rates （P < 0.05）. The tumor tissue cells were loosely arranged， with shrunken nuclei and numerous necrotic cells. Conclusion Safflower polysaccharide potentially inhibits the growth of colorectal cancer in mice through suppression of the PI3K/Akt/mTOR signaling pathway.