Background. A growing body of evidence suggests an altered role of epigenetic regulators like histone deacetylases (HDACs) in IPF. Targeting the epigenetic regulation by HDACs modulation could offer a promising approach to control and revert pulmonary fibrosis. Aims and objectives. Test the efficacy of Panobinostat, an FDA approved pan-HDAC inhibitor for the treatment of cancer, in a therapeutic Bleomycin (BLM) lung fibrosis rat model in comparison to a reference drug for IPF, Nintedanib (NINT). Methods. For pharmacokinetic (PK) and target engagment (TE) experiments, two groups of male naive SD rats received Panobinostat 10 mg/kg (IP) and were sacrified until 24 h and 72h post-dosing respectively. For efficacy experiment, male SD rats received a double intratracheally BLM administration or its vehicle (saline) on day 0 and day 4. According to therapeutic regimen, Panobinostat or NINT were administered from day 7 post-BLM at the respective doses of 1 and 3 mg/kg (IP, three times per week) and 100 mg/kg/day (oral, once daily) for three weeks. Automated histomorphometric analysis and biomarkers levels in lung homogenates were used to evaluate the efficacy of treatment. Results. The PK analysis indicated a high tissue partition after IP administration and a sustained target engagement (H3 acetylation quantification) supporting a less-frequent dosing respect to NINT. Panobinostat significantly reduced lung weight, pro-collagen-I, collagen-I and WISP-1 levels in lung homogenates and showed a trend in reduction of fibrotic area as highlighted by the histological analysis. Conclusions. Systemic administration of a pan-HDAC inhibitor demonstrated an anti-fibrotic effect comparable to that of NINT.