Current therapies for colorectal cancer (CRC) are associated with significant side effects and limitations, driving the search for novel therapeutic approaches. This study investigated the antiproliferative potential of D-limonene, a natural compound, on human colorectal adenocarcinoma (Caco-2) cells and analyzed its underlying mechanisms. Caco-2 cells were treated with D-limonene or doxorubicin (DOX) for 24 h. Cell viability was assessed using the MTT assay, with D-limonene and DOX showing IC50 values of 18.6 and 6.4 µM, respectively. In comparison to controls, D-limonene treatment dramatically enhanced the formation of reactive oxygen species (ROS) and decreased cellular antioxidant capacity, as seen by concentration-dependent lower glutathione (GSH) levels. The substance also increased the levels of pro-apoptotic proteins (caspase-3, Bax), tumor suppressor p53, lactate dehydrogenase (LDH), and inflammatory indicators [tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β)]. Furthermore, in a concentration-dependent way, D-limonene therapy decreased the levels of matrix metalloproteinases (MMP2, MMP9), proliferation marker Ki67, and the anti-apoptotic protein Bcl-2. These results imply that the induction of oxidative stress, inflammation, and apoptotic pathways mediates D-limonene's antiproliferative actions in colon cancer cells. Our findings show that D-limonene has therapeutic promise as a natural substitute for the treatment of colorectal cancer.