Aberrant activation of epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3) contributes to tumor progression and therapeutic resistance in colorectal cancer (CRC). Here, we investigated whether simultaneous inhibition of these pathways enhances anti-cancer efficacy. Human CRC cell lines HCT-116 and HT-29 were treated with the EGFR inhibitor Cetuximab and the STAT3 inhibitor Stattic alone or in combination. Dual treatment significantly reduced cell viability and colony formation compared with either monotherapy and exhibited synergistic effects. The combination inhibition markedly increased caspase-dependent apoptosis and induced G1/S cell cycle arrest. In addition, dual blockade suppressed migration. Collectively, these findings demonstrate that concurrent targeting of EGFR and STAT3 exerts synergistic anti-tumor activity in CRC cells.