Background: Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) are frequently linked. NAFLD has grown to be a major health problem. A glycoprotein called osteopontin (OPN) has been linked to the aetiology of NAFLD. Objective: This study aimed to determine if there is a connection between the level of plasma OPN and the occurrence of NAFLD in people with T2DM. Patients and Methods: This case-control study was conducted in the outpatient clinic of Internal Medicine Department at Benha University Hospital through the period between November 2022 and April 2023. It included 138 participants divided into three groups: Group 1 included 46 patients with NAFLD and T2DM, group 2 included 46 patients with NAFLD without T2DM, and group 3 that contained 46 healthy individuals as control group. Results: There were significantly higher plasma OPN concentrations in both groups 1 and 2 than in group 3. OPN levels were higher in group 1 compared to group 2. A positive correlation was found between OPN and body mass index (BMI) in both NAFLD groups. In group 2, plasma OPN correlated positively with uric acid and high-density lipoproteins (HDL) levels, while a negative correlation was observed with systolic blood pressure (SBP). Conclusion: Patient's with NAFLD and T2DM had higher plasma OPN levels more than those without diabetes who have NAFLD. Additionally, our study showed a favorable association between plasma OPN level and BMI, uric acid (UA), and HDL, suggesting that plasma OPN may have a role in the adjustment of the metabolic state.