Background: Actually, no specific treatment has been endorsed by FDA for non-alcoholic steatohepatitis (NASH). The present research aimed to evaluate the efficacy of PTX on NASH patients for 6 months compared to NASH patients who received regular treatment. Methods: We assigned a 6-month, open-labeled, randomized study to 50 NASH participants who were allocated into 2 groups; firstly, the control group, patients administered regular therapy. Secondly, in the treated group, patients received regular treatment plus pentoxifylline (PTX) at 400 mg thrice daily. To achieve this goal, liver aminotransferases tests, hematological biomarkers, lipid profile, fatty liver index (FLI), fibrosis-4 (FIB-4) index, aspartate aminotransferase to platelet ratio index (APRI) and NAFLD fibrosis score (NFS) were measured before and after 6-month of PTX-treatment. Results: The present study showed that PTX-treated patients significantly decreased hepatic levels of aminotransferase enzymes and non-invasive scores. Besides, after 6 months of treatment, PTX revealed improvement in hepatic fibrosis through a marked reduction in aspartate aminotransferase to platelet ratio (APRI) index, fibrosis-4 (FIB‐4) index, and NAFLD fibrosis score (NFS). Conversely, other biochemical markers showed a slightly significant change after PTX therapy. Moreover, PTX administration showed non-significant safety problems in these participants. Conclusions: Patients treated with PTX revealed safety and efficacy in improving liver enzymes, lipid panel, and non-invasive fibrosis scores in NASH patients. In addition, our results indicated that PTX showed improvement in hepatic fibrosis scores, which reflected its anti-fibrotic activity.