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Background: Osteosarcoma (OS) is a common malignant cancer in children and adolescents and has a cure rate that has not improved in the last two decades. CYT997 (lexibulin) is a novel potent microtubule-targeting agent with various anticancer activities, such as proliferation inhibition, vascular disruption, and cell cycle arrest and apoptosis induction, in multiple cancers. However, the direct cytotoxic mechanisms of CYT997 have not yet been fully characterized. Methods: We evaluated apoptosis and autophagy in human osteosarcomas after treatment with CYT997 and investigated the underlying mechanisms. To explore relationships, we used the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC), PERK inhibitor GSK2606414, ERO1 inhibitor EN460 and mitochondrial targeted protection peptide elamipretide. BALB/c-nu mice were inoculated with 143B tumor cells to investigate the in vivo effect of CYT997. Results: We explored the efficacy and mechanism of CYT997 in osteosarcoma (OS) in vitro and in vivo and demonstrated that CYT997 potently suppresses cell viability and induces apoptosis and autophagy. CYT997 triggered production of ROS and exerted lethal effects via endoplasmic reticulum (ER) stress in OS cells. NAC attenuated these effects. The PERK inhibitor GSK2606414, which can block the ER stress pathway, reduced ROS production and enhanced cell viability. Moreover, activation of ERO1 in the ER stress pathway was responsible for inducing ROS production. ROS produced by the mitochondrial pathway also aggravate ER stress. Protection of mitochondria can reduce apoptosis and autophagy. Finally, CYT997 prominently reduced tumor growth in vivo. Conclusions: This study suggests that CYT997 induces apoptosis and autophagy in OS cells by triggering mutually enhanced ER stress and ROS and may thus be a promising agent against OS. [ABSTRACT FROM AUTHOR]