Background: Colorectal cancer is the third most common cancer and the second most common cause of cancer-related death worldwide. Common treatments for colorectal cancer include chemotherapy, surgery, immunotherapy, etc. One of the chemotherapy drugs is doxorubicin, but it has many side effects. Recently, the antibacterial and anticancer effects of Satureja khuzistanica (S. khuzistanica) extract have been proven. Probiotics have been used in recent years to change the intestinal microbiome and treat colon cancer and reduce the side effects of treatments. Material and Methods: In this study, the viability of HT29 colorectal cancer cells was examined using MTT after treatment with the study groups, and the expression of BAX, BCL2, SMAC, P53, MMP9, CASP9, and SUR genes was evaluated by Real time PCR. Results: The results showed that the expression of BAX, SMAC, P53, and CASP9 genes increased by 4.21, 3.055, 5.105, and 2.216 (p<0.0001) compared to the control after treatment with S. khuzistanica, respectively. The expression of BCL2, MMP2, SUR and MMP9 genes decreased by 1.1% after treatment with S. khuzistanica compared to the control. The results also showed that the combined treatment of S. khuzistanica with Nisin or doxorubicin had a greater effect on changes in gene expression. Conclusion: This study could be a therapeutic strategy for using natural substances such as S. khuzistanica extract and probiotic Nisin to reduce the dose of chemotherapy.