Although the introduction of immune- and targeted-therapy has improved the clinical response and outcomes, lung cancer remains a therapeutic challenge. Developing new therapeutics is necessary to improve the treatment of lung cancer. Here, we show that ribavirin, a clinically available anti-viral drug, is an attractive candidate for lung cancer treatment. We show that ribavirin is active against a panel of lung cancer cell lines regardless of molecular and cellular heterogeneity. Notably, the effective concentrations of ribavirin are clinically achievable, display minimal toxicity to normal cells and synergistic effect with paclitaxel. Its potent efficacy and synergism with chemotherapy on cancer cell, and minimal toxicity on normal cells are observed in lung xenograft mouse model. Ribavirin is also an angiogenesis inhibitor as it inhibits capillary network formation, growth and survival of human lung tumor-associated endothelial cell (HLT-EC). The mechanism studies demonstrate that ribavirin acts on lung cancer cells via suppressing eIF4E and mTOR signaling, leading to the subsequent inhibition of eIF4E-mediated protein translation. Our work suggests that ribavirin has advantage than many anti-cancer agents by targeting both tumor cells and angiogenesis. Our work also highlights the therapeutic potential of ribavirin for the treatment of lung cancer. (C) 2020 Elsevier Inc. All rights reserved.