Asthma, a chronic respiratory disease is characterized by airway inflammation, remodelling, airflow limitation and hyperresponsiveness. At present, it is considered as an umbrella diagnosis consisting several variable clinical presentations (phenotypes) and distinct pathophysiological mechanisms (endotypes). Recent evidence suggests that oxidative stress participates in airway inflammation and remodelling in chronic asthma. Opioids resembled by group of regulatory peptides have proven to act as an immunomodulator. β-Endorphin a natural and potent endogenous morphine produced in the anterior pituitary gland play role in pain modulation. Therapeutic strategy of many opioids including β-Endorphin as an anti‑inflammatory and antioxidative agent has not been yet explored despite its promising analgesic effects. This is the first study to reveal the role of β-Endorphin in regulating airway inflammation, cellular apoptosis, and oxidative stress via Nrf-2 in an experimental asthmatic model. Asthma was generated in balb/c mice by sensitizing with 1% Toulene Diisocyanate on day 0, 7, 14 and 21 and challenging with 2.5% Toulene Diisocyanate from day 22 to 51 (on every alternate day) through intranasal route. β-Endorphin (5 µg/kg) was administered through the nasal route 1 h prior to sensitization and challenge. The effect of β-Endorphin on pulmonary inflammation and redox status along with parameters of oxidative stress were evaluated. We found that pre-treatment of β-Endorphin significantly reduced inflammatory infiltration in lung tissue and cell counts in bronchoalveolar lavage fluid. Also, pre-treatment of β-Endorphin reduced reactive oxygen species, Myeloperoxidase, Nitric Oxide, Protein and protein carbonylation, Glutathione Reductase, Malondialdehyde, IFN-γ, and TNF-α. Reversely, β-Endorphin significantly increased Superoxide dismutase, Catalase, glutathione, Glutathione-S-Transferase, and activation of NF-E2-related factor 2 (Nrf-2) via Kelch-like ECH-associated protein 1 (Keap1), independent pathway in the lung restoring architectural alveolar and bronchial changes. The present findings reveal the therapeutic potency of β-END in regulating asthma by Keap-1 independent regulation of Nrf-2 activity. The present findings reveal the therapeutic potency of β-Endorphin in regulating asthma.