Signal transducer and activator of transcription 3 (STAT3) signaling is a major driver of colorectal cancer (CRC) growth, however therapeutics, which can effectively target this pathway, have so far remained elusive. Here, we performed an extensive screen for STAT3 inhibitors among a library of 1167 FDA-approved agents, identifying Ponatinib as a lead candidate. We found that Ponatinib inhibits STAT3 activity driven by EGF/EGFR, IL-6/IL-6R and IL-11/IL-11R, three major ligand/receptor systems involved in CRC development and progression. Ponatinib was able to inhibit CRC migration and tumor growth in vivo. In addition, Ponatinib displayed a greater ability to inhibit STAT3 activity and mediated superior anti-proliferative efficacy compared to five FDA approved SRC and Janus Kinase (JAK) inhibitors. Finally, long-term exposure of CRC cells to Ponatinib, Dasatinib and Bosutinib resulted in acquired resistance to Dasatinib and Bosutinib occurring within six weeks. However, acquired resistance to Ponatinib was observed after long-term exposure of >4 months. Overall, our results identify a novel anti-STAT3 property of Ponatinib and thus, Ponatinib offers a potential therapeutic strategy for CRC.