Chronic obstructive pulmonary disease (COPD), characterised by persistent airflow limitation during breathing, is considered to be the third leading cause of death worldwide. Among the mechanisms involved in this pathology is the excessive generation of neutrophil extracellular traps (NETs), which can induce an unwanted inflammatory response. These traps have been reported to be generated by the enzyme peptidyl arginine deiminase 4 (PAD4). The aim of this work is therefore to evaluate the effect of the administration of a siRNA targeting PAD4 on lung damage in a COPD animal model. Wistar rats weighing 300–350 g were administered cadmium chloride (5 mg/kg i.p.) every 24 h. Then, following one week of the administration of cadmium chloride, the PAD4-targeted siRNA was administered, and at the second week, lung function was measured, as were lung and heart weights, as well as PAD4 expression by RT-PCR. Our results showed that cadmium administration generated a COPD model, which increased PAD4 expression and decreased lung and heart weights and respiratory function. SiRNA administration partially reversed the changes associated with the COPD model. In conclusion, our results suggest that administration of an siRNA targeting PAD4 could improve respiratory function by decreasing lung and heart damage.