Colorectal cancer is a highly aggressive metastatic cancer with poor clinical outcomes. Terfenadine in this study significantly suppressed the cell viability of HCT116 cells, which was recovered partially when histamine or 2-pyridyl ethylamine was pretreated. Expression of pro-apoptotic protein Bax, cleaved caspase-3, and poly-(ADP-ribose) polymerase (PARP) were also increased, and anti-apoptotic protein Bcl-2 was decreased on terfenadine treatment, thereby releasing cytochrome c in HCT116 cells. Additionally, terfenadine treatment increased p53 expression by downregulating Murine Double Minute-2 (Mdm2). The activation of JAK2, ERK1/2, and MEK1/2, along with STAT3\'s phosphorylation, were also reduced by terfenadine treatment, thereby downregulating the expression of survivin, cyclin D1, cyclin D2, and cyclin D3. Also, the MEK inhibitor U0126 and the JAK2 inhibitor AG490, when treated, significantly reduced ERK1/2 and JAK2 phosphorylation, respectively, causing STAT3 downregulation. Terfenadine treatment also decreased the complex formation between β-arrestin 2 and MEK1/2 kinase. Terfenadine suppresses the phosphorylation of PKC substrates, and the phosphorylation of MEK1/2 and ERK1/2 kinases was significantly reduced when treated with Ro 31-8220 (a PKC inhibitor). Additionally, terfenadine abrogated the growth of HCT116 tumor xenografts. Overall, our research shows that terfenadine may induce apoptosis in human HCT116 colorectal cancer cells by blocking STAT3 signaling.