Nanotechnology allows drugs to be delivered locally and specific cells to be targeted, leading to a promising new therapeutic approach for interstitial lung fibrosis. Hyaluronic acid (HA)-decorated imatinib-loaded liposomes (LIP-HA44700-Im) are developed to target CD44 positive cells for the inhalation treatment of fibrogenic lung disorders. LIP-HA44700-Im are assessed for their uptake and biological activity on respiratory effectors that are related to CD44 expression and compared to undecorated liposomes (LIP). LIP-HA44700-Im uptake is significantly higher than that of LIP, and most of the internalized LIP-HA44700-Im are colocalized with cellular endosomes. LIP-HA44700-Im also reduce lung fibroblasts viability. After 24 h, LIP-HA44700-Im are able to impair collagen 1a1 release and c-Abl phosphorylation. Based on in vitro data, it has been assessed whether the intratracheal administration of LIP-HA44700-Im is able to prevent lung fibrosis in a mouse bleomycin model. The local administration of LIP-HA44700-Im is associated with a significant decrease in alveolar inflammation, lung fibrosis, collagen deposition, and TGF-β expression. LIP-HA44700-Im target and deliver imatinib to lung pathogenic cells in vitro and represent a promising therapeutic option for the local treatment of fibrogenic lung disorders, although further development is required. These in vivo results confirm the validity of targeted nano-based treatment for inflammatory-driven lung fibrogenesis.