Squamous cell lung carcinoma (SQCLC) is an aggressive type of lung cancer. In contrast with the marked advances that have been achieved in the treatment of lung adenocarcinoma, there are currently no effective targeted therapies for SQCLC, for with cytotoxic drugs are still the main treatment strategy. Therefore, the present study aimed to develop novel combination therapies for SQCLC. The results demonstrated that a combined treatment with the potent histone deacetylase (HDAC) inhibitor OBP‑801 and the third‑generation anthracycline amrubicin synergistically inhibited the viability of SQCLC cell lines by inducing apoptosis signal‑regulating kinase 1 (ASK1)‑dependent, as well as JNK‑ and p38 mitogen‑activated protein kinase (MAPK)‑independent apoptosis. OBP‑801 treatment strongly induced the protein expression levels of thioredoxin‑interacting protein (TXNIP), and amrubicin treatment increased the levels of intracellular reactive oxygen species (ROS), which suggested that this combination oxidized and dissociated thioredoxin 2 (Trx2) from mitochondrial ASK1 and activated ASK1. Moreover, mouse xenograft experiments using human H520 SQCLC cells revealed that the co‑treatment potently suppressed tumor growth in vivo. These results suggested that a combined treatment with OBP‑801 and amrubicin may have potential as a therapeutic strategy for SQCLC.