An increasing number of reports have suggested the use of hydroxychloroquine (HCQ) as an adjunct anti-cancer treatment to enhance the chemotherapeutic response, as well as for the treatment of several fibrotic skin diseases and cystic fibrosis. In this study, we synthesized a cholesterol-modified HCQ (Chol-HCQ) and hypothesized that a systemic delivery system with Chol-HCQ nanocarriers could be effective for the treatment of bleomycin-induced pulmonary fibrosis. Chol-HCQ significantly inhibits the proliferation of rat lung fibroblasts, regulates inflammation and ameliorates bleomycin-induced pulmonary fibrosis in rats. It regulates the expression of pro-inflammatory cytokines, such as TNF-α; reduces the infiltration of inflammatory neutrophils; and inhibits the phosphorylation of NF-κB. Chol-HCQ also reduces the expression of connective tissue growth factor (CTGF) and phosphorylation of extracellular regulated protein kinase (p-ERK) in rats with bleomycin-induced pulmonary fibrosis. Chol-HCQ nanocarriers reduce early pulmonary inflammation and inhibit the CTGF/ERK signalling pathway in bleomycin-induced pulmonary fibrosis. These results demonstrate that Chol-HCQ liposomes suppress pulmonary inflammation and reduce pulmonary fibrosis induced by bleomycin. The systemic administration safety of Chol-HCQ liposomes was confirmed after intravenous administration for 28 days in rats. The present study provides evidence that Chol-HCQ liposomes may be a potential therapeutic agent for inflammation associated with pulmonary fibrosis.