Excessive or dysregulated inflammation can lead to Chronic inflammatory respiratory diseases (CIRDs), such as Chronic Obstructive Pulmonary Disease (COPD) and asthma, which are significant global health concerns characterized by persistent airway inflammation and tissue damage. While conventional treatments have been effective, they are often associated with severe side effects driving the search for safer, natural alternatives. Nobiletin, a flavonoid derived from citrus peels, has emerged as a promising candidate due to its potent anti-inflammatory. It’s clinical application is hindered by poor water solubility, low oral bioavailability, and extensive first-pass metabolism. To address these limitations, this study explores the use of Nanostructured Lipid Carriers (NLCs) as an innovative mechanism of delivery for nobiletin. This research focused on formulating and characterizing nobiletin-loaded NLCs (Nob-NLC) to optimize their physicochemical properties and evaluate their efficacy in targeting respiratory inflammation using mouse macrophage cell line (RAW 264.7). The optimized formulation exhibited desired particle characteristics and a sustained release demonstrating its potential for enhanced therapeutic efficacy. In vitro studies revealed that Nob-NLC when compared to free nobiletin, demonstrated a greater anti-inflammatory action. Nob-NLC in the incubation significantly decreased the production of Nitric Oxide to 26.5 ± 0.27 μM (41.3 % decrease compared to LPS alone, p < 0.0001) and Reactive Oxygen Species 76.5% (108.5 ± 0.32 μM, p < 0.0001 vs. LPS alone). Furthermore, it reduced the mRNA expression of pro-inflammatory cytokines : reducing TNF-α expression by 69.1% (0.34 ± 0.02, p < 0.0001 vs. LPS-only group) and IL-6 expression by 42.5% (0.62, p < 0.0001 vs. LPS-treated group. The difference between action of pure nobiletin and Nob-NLC were statistically significant (p < 0.0001) in all in vitro studies except the Nitric Oxide study (p > 0.05). The results underscore the potential of nobiletin-loaded NLCs as an effective treatment strategy for managing CIRDs.