Aims: Cigarette smoking (CS) is the main cause of chronic obstructive pulmonary disease (COPD). Endothelial dysfunction is related to the severity of pulmonary disease in COPD. This study aimed to evaluate the effectiveness of single and combined administration of pioglitazone (Pio) and irbesartan (Irb) against COPD-induced endothelial dysfunction in mice and the involvement of NO and H2S in their effects. Materials and methods: Adult male Swiss mice (n = 40, weighing 25–30 g) were assigned into 5 groups. The normal control group received 1% carboxy methyl cellulose (CMC). The CS group was exposed to CS and administered 1% CMC for 3 months. The CS + Pio, CS + Irb, and CS + Pio/Irb groups were subjected to CS and received Pio (60 mg/kg), Irb (50 mg/kg), and their combination respectively, daily orally for 3 months. Body weight gain, mean blood pressure, urinary albumin, serum NO and ET-1 levels with TNF-α and IL-2 levels in lung tissue and bronchoalveolar lavage were measured. Lung H2S and ET-1 levels, protein expression of PPARγ in lung and VEGF in lung and aortic tissues with histological changes were assessed. Key findings: Our results illustrated that CS induced a model of COPD with endothelial dysfunction in mice. Pio/ Irb singly and in combination elicited protective effects against the pathophysiology of the disease with more improvement in the combined group. There is a strong correlation between NO and H2S as well as the other measured parameters. Significance: Collectively, both drugs performed these effects via their anti-inflammatory potential and increasing H2S and NO levels.