Background: Colorectal cancer is one of the chief causes of death and morbidity among all types of cancer worldwide, comprising both sexes. Crocetin (CT) is a major phytoconstituent of Crocus sativus L. which performed a number of pharmacological activities. The current study established CT's anticancer effect against 1,2-dimethylhydrazine (DMH)-persuaded colorectal cancer and discovered likely in vivo mechanisms. Methods: To tempt colorectal cancer in experimental albino Wistar rats, DMH was inserted subcutaneously. The rats were separated into five groups as follows: Group I – normal control rats, Group II – DMH-treated rats, Group III – DMH-treated rats receiving CT (5 mg/kg), Group IV – DMH-treated rats receiving CT (10 mg/kg), and Group V – DMH-treated rats receiving CT (20 mg/kg) for 10 weeks. At consistent intervals, the body weight and tumor weight were assessed. Biochemical, hepatic, antioxidant, Phase II antioxidant enzymes, inflammatory mediators, cytokine parameters, and apoptosis markers were projected at the end of the experimental study. Results: CT treatment suggestively augmented body weight (P < 0.001) and reduced tumor weight. CT administration also changed the level of antioxidant parameters – superoxide dismutase, glutathione peroxidase, and glutathione reductase; Phase I enzymes – cytochrome B5 and cytochrome P450; and Phase II enzymes – glutathione-S-transferase and UDP-glucuronyltransferase, respectively. Attained results also reveal that CT treatment abridged the level of cyclooxygenase-2, prostaglandin-2, and nitric oxide and diminish the expression of p38 mitogen-activated protein kinases. CT also augmented the expression of apoptosis markers – caspase-3 and caspase-9. Conclusion: Thus, the complete outcomes recommended the chemoprotective role of CT against DMH-induced colorectal cancer through the inhibition of inflammation and apoptosis pathways.