Inflammation and oxidative stress have been suggested as an important pathogenesis of chronic obstructive pulmonary disease (COPD). We investigated the effect of YPL-001, the drug substance of Pseudolysimachion rotundum var. subintegrum , on cigarette smoke extract (CSE)-induced inflammation and anti-oxidative pathway in human bronchial epithelial cells. CSE induced interleukin-8 (IL-8) which was significantly suppressed by YPL-001. YPL-001 also suppressed IL-17A-induced IL-8 release, which suggests that the inhibitory effect of YPL-001 on IL-8 production is not CSE stimulation-specific. NF-κB is a major transcription factor that regulates the expression of several genes including inflammatory cytokines. Although YPL-001 did not block nuclear translocation of NF-κB subunit p65, it suppressed transcriptional activity of NF-κB by blocking acetylation of p65 (Lys310) and suppressed CSE or IL-17A-induced transcription of IL-8 gene. Histone deacetylases (HDACs) prevent gene transcription by condensing DNA structure and affecting NF-κB nuclear binding. YPL-001 alone increased HDAC activity and enhanced CSE-induced activation of HDAC. YPL-001-induced suppression of NF-κB transcriptional activity might be caused by increase in HDAC activity. Moreover, we found that YPL-001 increased Nrf2 expression via both degradation of its inhibitory protein, Keap1 and de novo protein synthesis, resulting in nuclear translocation of Nrf2. YPL-001 increased DNA binding activity of Nrf2. Consequently, YPL-001 up-regulated the expression of Nrf2-targeted anti-oxidant genes such as NQO1 and HO-1. Altogether, these results suggest that YPL-001 could be a good therapeutic candidate for treatment of COPD.