Diabetes mellitus (DM) is a chronic condition associated with raised levels of blood glucose due to the body cannot produce any or enough insulin hormone or cannot be effectively utilized the produced insulin by the body. Patients with poorly controlled diabetes show a significant alteration in various parameters including metabolic, cellular, immunological, and hematological disturbances that leads to vascular complications. Thus, the main aim of this study is to compare hematological parameters between type 2 diabetes mellitus (T2DM) patients and healthy controls. A comparative cross-sectional study was conducted in Dessie comprehensive specialized hospital from January to June 2021. A total of 240 study participants consisting of 120 T2DM patients and 120 healthy controls were recruited using a systematic random sampling technique. Hematological parameters were determined using the DIRUI BF6500 automated hematology analyzer. Independent T-test was used to compare the mean of hematological parameters between T2DM patients and healthy controls. Pearson correlation test was used to determine the correlation between FBG, BMI, SBP, DBP, and hematological parameters in T2DM patients. Multivariate logistic regression was used to assess the association between socio-demographic and clinical variables with anemia. The result was expressed in mean and standard deviation and presented in texts and tables. P-value < 0.05 was considered to be statistically significant. The mean and standard deviation of monocyte count, basophil count, monocyte %, basophil %, RBC count, hematocrit, MCV, MCH, RDW-SD, MPV, PDW, PLC-R, and plateletcrit showed a significant difference between T2DM patients and healthy control group. Pearson correlation coefficient showed that the total WBC count, neutrophil count, monocyte count, basophil count, RDW-CV, PDW, MPV, PLC-R, and plateletcrit were statistically positively correlated with FBG whereas RBC count, Hgb, hematocrit, MCV, MCH, and RDW-SD were statistically negatively correlated with FBG in T2DM patients. Moreover, total WBC count, neutrophil count, monocyte count, basophil count, Hgb, and plateletcrit were statistically positively correlated with BMI while RBC count, Hgb, hematocrit, MCV, MCH, and RDW-SD were statistically negatively correlated with BMI in T2DM patients. On the other hand, DBP was significantly positively correlated with platelet count and RDW-CV whereas SBP also significantly positively correlated with total WBC count, neutrophil count, basophil count, and PDW. Besides, DBP and SBP showed statistically significant negative correlations with RBC count, Hgb level, and Hct value in T2DM patients. The overall prevalence of anemia was 25.8% in T2DM patients with a higher prevalence of anemia (16.7%) in female patients. Multivariate logistic regression revealed that being non-employee worker (AOR: 3.6, 95% CI, 1.4-46.0, P = 0.002), presence of neuropathy (AOR: 13.40, 95% CI, 6.83-26.28, P = 0.00), and duration of the disease ≥ 5 years (AOR = 3.2, 95% CI, 1.2-15.3, P = 0.03) have had statistically significant association with anemia inT2DM patients. Patients with T2DM may have significant alterations in various hematological parameters. Hematological parameters should be regularly tested for early diagnosis and proper management of diabetes-related complications.