BACKGROUND: Melatonin has important effects on inflammation responses and could be a possible therapeutic target for asthma, COPD and asthma-COPD overlap (ACO). OBJECTIVE: To evaluate melatonin treatment in lung hyperresponsiveness, inflammation and oxidative stress responses in models of asthma, COPD and ACO. METHODS: Experimental groups: ELA: received Elastase; OVA: received ovalbumin intraperitoneally and inhalation of ovalbumin; ACO: received elastase and ovalbumin intraperitoneally and inhaled; SAL: received saline; ELA+MEL, OVA+MEL and ACO+MEL: groups were submitted to the experimental protocols previously described and melatonin for 6 days. After 28 days, we evaluated: lung hyperresponsiveness to methacholine, exhaled nitric oxide (eNO) and cell expression of MMP-9, TIMP-1, TGF-Beta, IL-5, IL-17, iNOS. RESULTS: eNO and airway resistance (%Raw) showed no difference. Maximal responses to methacholine of: resistance of respiratory system (%Rrs), elastance of respiratory system (%Ers), lung tissue resistance (%Gtis), lung tissue resistance (%Htis) and airway resistance (%Raw) were decreased in ACO compared to ACO-MEL (p<0.05). A reduction in the using immunohistochemistry of MMP-9, TIMP-1, TGF-Beta, IL-5, IL-17, iNOS and NF-kB was observed in the treated groups compared to non-treated animals (Table 1). CONCLUSION: Melatonin attenuated pulmonary hyperresponsiveness, oxidative stress and lung inflammation in these models.