Purpose This study aimed to reveal the prospective interplay between sitagliptin and hematological parameters in Ty2-DM, to provide insightful modalities for optimized patients’ care. Methods A retrospective cohort study that was conducted in private clinics and enrolled a total of 135 participants during December 2023 to April 2024. The patients were divided into three groups; group 1 (the control group) included 45 healthy individuals, group 2 consisted of 45 Ty2-DM patients on 1000mg metformin daily as a monotherapy, and group 3 included 45 Ty2-DM on a combination of 50mg sitagliptin plus 1000 mg metformin daily. Blood samples were collected from all participant to estimate the values of glycemic status, renal and liver functions, complete blood count (CBC), ferritin, and erythropoietin (EPO). Results Fasting serum glucose (FSG) was significantly lower in group 2 compared to group 3 (p=0.005) whereas no significant value in HbA1c was observed between group 2 and group 3. Renal and liver function parameters were comparable in the two patient groups. Group 3 had higher hemoglobin (Hb) (p=0.006), ferritin (p=0.02), and red blood cells (RBCs) (p=0.004), in comparison to group 2. Additionally, in group 3, the correlation analysis showed a significant inverse relationship between ferritin and EPO, with a significant direct association between ferritin and Hb, RBCs, hematocrit (Hct), and mean corpuscular volume (MCV) respectively. Conclusion The study highlights the potential of sitagliptin to alter hematological parameters in Ty2-DM patients, this effect is closely correlated with ferritin level rather than concomitant changes in renal or liver functions.