Background: Non-Alcoholic Fatty Liver Disease (NAFLD) and Type 2 Diabetes (T2D) are highly prevalent diseases worldwide. Insulin Resistance (IR) is the common denominator of the two conditions even if the precise timing of onset is unknown. Lifestyle change remains the most effective treatment to manage NAFLD. This study aimed to estimate the effect of the Low Glycemic Index Mediterranean Diet (LGIMD) and exercise (aerobic and resistance) over a one-year period on the longitudinal trajectories of glucose metabolism regulatory pathways. Materials and Methods: In this observational study, 58 subjects (aged 18–65) with different degrees of NAFLD severity were enrolled by the National Institute of Gastroenterology—IRCCS “S. de Bellis”, to follow a 12-month program of combined exercise and diet. Results: The mean age was 55 ± 7 years old. Gender was equally distributed among NAFLD categories. There was a statistically significant main effect of time for glycosylated hemoglobin (Hb1Ac) over the whole period (−5.41, 95% CI: −7.51; −3.32). There was a steady, statistically significant decrease of HbA1c in participants with moderate and severe NAFLD whereas this effect was observed after the 9th month in those with mild NAFLD. Conclusions: The proposed program significantly improves glucose metabolism parameters, especially HbA1c.