Natural products have gained considerable interests because of their use in some industrial areas including nutrition, cosmetic, pharmacy, and medicine. Salvia fruticosa M. (Lamiaceae) is known for its antioxidant, antimicrobial, and antiproliferative activities. Phase I xenobiotic metabolizing enzymes, CYP1A2 and CYP2E1, produce reactive metabolites which are eliminated by the action of phase II enzymes, NQO1, GPx, and glutathione S-transferases (GSTs). In this study, in vitro modulatory effects of S. fruticosa and its major phenolic compound rosmarinic acid (RA) on CYP1A2, CYP2E1, NQO1, GPx, and GSTm1 mRNA expressions and enzyme activities of GPx and GSTs were investigated in HT-29 cells. An mRNA expression analysis revealed that CYP1A2 and CYP2E1 levels were decreased while those of NQO1, GPx, and GSTm1 increased after S. fruticosa and RA treatments. In parallel to gene expressions, enzyme activities of GPx and GSTs by S. fruticosa increased 1.68- and 1.48-fold, respectively. Moreover, RA increased GPx and GSTs activities 1.67- and 1.94-fold, respectively. The results of this preliminary study show that metabolism of xenobiotics may be altered due to changes in the expression and activity of the investigated enzymes by S. fruticosa.