Corticosteroid resistance is the essential obstacle for effective treatment of chronic obstructive pulmonary disease (COPD). Oxidative stress and persistent chronic inflammation caused by cigarette smoke are likely to induce this corticosteroid insensitivity. Salidroside (Sal) is a main ingredient of traditional Chinese medicine rhodiola, which has the effects of anti-oxidation and anti-inflammatory. We aimed to investigate the role of Sal in the corticosteroid sensitivity of COPD. Collecting peripheral blood mononuclear cells (PBMC) from healthy volunteers (HV) and patients with COPD, and human monocytic U937 cells stimulated by normal culture and cigarette smoke extract (CSE), corticosteroid sensitivity was determined as the dexamethasone concentration causing 30% inhibition of tumor necrosis factor alpha (TNF-α)-induced IL-8 production (Dex-IC ₃₀) in these cells. Compared with PBMC from HV and normally cultured U937, in PBMC from COPD patients and U937 cells stimulated by CSE, the inhibitory effect of dexamethasone on IL-8 was weakened and the levels of nuclear factor erythroid 2‐related factor 2 (Nrf2) and histone deacetylase‐2 (HDAC2) was reduced. In conclusion, Sal restored dexamethasone inhibition of IL‐8 production, accompanied by raising the expression of Nrf2 and HDAC2 levels. Sal may upregulate HDAC2 expression by activating the Nrf2/HO-1 signaling pathway, and then restore corticosteroid sensitivity in COPD.