Zataria multiflora Boiss., with the common name Avishan-e-Shirazi, is native to Iran. This herb has been found to possess varied pharmacological properties. In the present study, for the first time, colon chemopreventive effects of Z. multiflora essential oils (0.01% and 0.1% in the diet) in rats treated with 1,2-dimethylhydrazine (DMH) were demonstrated. For this purpose, the oxidative stress/antioxidant parameters (lipid peroxidation, glutathione, superoxide dismutase, catalase, and ferric reducing ability of plasma) concomitant with xenobiotic metabolizing enzymes (CYP450 and GST) were considered. Moreover, the colonic β-catenin protein was examined in colon tissues followed by histopathological analysis. The results showed that the dietary intervention of Z. multiflora oils in tumor-bearing rats induced with DMH caused significant modulatory effects on DMH-metabolizing enzymes, but with lack of oxidative stress/antioxidant status. In parallel, the elevated protein β-catenin induced by DMH decreased significantly in treatment groups. However, the decreased tumor formations in histopathological biopsies in treated groups further confirmed these results. Thus, with reference to histopathological and biochemical data, it can be safely concluded that inhibition of colon premalignant lesions induced by DMH was mediated by the interference of Z. multiflora oils through the modulatory effect of DMH-metabolizing enzymes in association with β-catenin and no impact of antioxidant/oxidative stress state.