Diabetes mellitus (DM) is a metabolic disorder marked by hyperglycemia, caused by impaired insulin secretion and activity. Chronic inflammation holds a significant role in the development, progression, and complications of DM and obesity. There are publications reporting that the monocyte/ high-density lipoprotein (HDL)-C ratio (MHR) and plasma atherogenic index (PAI) could be used as indicators of systemic inflammation. In the present study, we aimed to explore the effect of empagliflozin, an inhibitor of sodium-glucose co-transporter 2 (SGLT2), on MHR and PAI in obese and non-obese type 2 diabetes mellitus (T2DM) patients. A total of 125 patients who presented to the outpatient clinics of Tokat Gaziosmanpasa University Hospital between January 2019 and January 2023 with a diagnosis of T2DM and were started on 25 mg empagliflozin and used for a minimum of 24 weeks were included in the study. The patients' age varied between 18-75 years, were without chronic liver disease, chronic renal failure, infection, or inflammatory disease, and were not on drugs affecting bone marrow. The patients were categorized into two groups, obese and non-obese, according to their body mass index (BMI). The data obtained were statistically analyzed using the IBM SPSS Statistics 25 software package. The mean age of the patients was 57.5 ± 10.9 years. Of the patients, 59.2% (n = 74) were female, and 40.8% (n = 51) were male. The mean HbA1c percentage was 8.99 ± 2.18% prior to empagliflozin treatment and significantly decreased to 7.68 ± 1.80% after empagliflozin use (p < 0.05). The mean monocyte HDL-C ratio (MHR) pre- and post-empagliflozin treatment was 16.22 ± 6.31 and 13.77 ± 5.29, respectively, and these values significantly differed from each other (p < 0.05). The mean plasma atherogenic index (PAI) of the patients before empagliflozin treatment was 0.62 ± 0.28, whereas, after the treatment, it significantly reduced to 0.52 ± 0.27 (p < 0.05). While MHR and PAI statistically significantly decreased with the use of empagliflozin, there was no difference between the obese and non-obese patient groups in terms of MHR and PAI results. Studies in the literature show that the decrease in MHR and PAI leads to a decline in inflammation. MHR and PAI are inexpensive and practical markers to assess cardiovascular disease risk and inflammation in diabetic patients. This finding indicates that MHR and PAI can be used as inflammation markers in patients on empagliflozin treatment.