Colorectal cancer represents a major global health challenge, ranking third in incidence and second in cancer-related mortality. Emerging evidence highlights dopamine receptor-2 (DRD2) as a key player in oncogenic signaling. In this study, we investigated the anticancer effects of aripiprazole (ARP), a DRD2 partial agonist, in human colorectal cancer HCT116 cells. ARP significantly induced reactive oxygen species (ROS) accumulation and reduced cell viability in a concentration-dependent manner. This effect was partially reversed by co-treatment with the DRD2 antagonist domperidone or the ROS scavenger NAC. Mechanistically, ARP downregulated Bcl-xL expression, impairing mitochondrial integrity and promoting cytochrome C release, which activated caspase-mediated apoptosis. Furthermore, ARP enhanced p53 expression and reduced Mdm2 levels. It inhibited MEK1/2 and JAK2 phosphorylation, leading to STAT3 inactivation and reduced expression of STAT3 target genes, such as survivin, cyclin D2, and cyclin D3. Pharmacological inhibition of MEK1/2 or JAK2 mimicked ARP’s effects, confirming the involvement of these pathways in our experimental set-up. These results position ARP as a potent inducer of apoptosis in HCT116 cells through ROS-mediated STAT3 inhibition and mitochondrial dysfunction, highlighting its therapeutic potential in colorectal cancer treatment.