Background <p>Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in type 2 diabetes mellitus (T2DM), with shared pathophysiological mechanisms, including insulin resistance, oxidative stress, and inflammation.</p> Objectives <p>This study evaluates the effects of vitamin E and ertugliflozin, individually and in combination, alongside standard pioglitazone therapy, on hepatic and metabolic parameters in patients with NAFLD and T2DM.</p> Methods <p>A 24-week, double-blind, randomized, controlled clinical trial on 173 patients with NAFLD and T2DM was assigned into four groups: vitamin E (<i>n</i> = 42), pioglitazone (<i>n</i> = 43), ertugliflozin (<i>n</i> = 44), and vitamin E + ertugliflozin (<i>n</i> = 44) combination therapy. The primary outcome was to monitor changes in&#xa0;liver steatosis assessed via ultrasound. Secondary outcomes included&#xa0;evaluation of liver enzymes, glycemic control, fibrosis markers,&#xa0;and lipid profiles.</p> Results <p>Combination therapy of vitamin E + ertugliflozin showed the highest decrease in liver fat content, with 11 participants achieving successful Grade 0 (<i>p</i> &lt; 0.001). Significant improvements were also observed in glycemic control, HbA1c, triglycerides, and liver enzymes. Ertugliflozin monotherapy showed significant efficacy in improving liver enzymes, glycemic parameters, and fibrosis markers. Pioglitazone improved the initial stage of NAFLD but had a limited impact on advanced fibrosis. Ertugliflozin, in combination with vitamin E, decreases oxidative stress; however, vitamin E by itself has no impact on the metabolic and fibrosis index.</p> Conclusion <p>The ertugliflozin and vitamin E combination is a very effective treatment for patients with NAFLD and T2DM. It improves hepatic steatosis and metabolic indicators. Exploration is required for combination therapy in order to assess the prolonged efficacy and safety of the treatment.</p>