Background. Schistosomiasis is a parasitic disease that resides in the vascular system of vertebrates, causing a chronic, debilitating disease that affects more than 200 million people and 800,000 deaths per year in over 70 countries. This parasite causes liver dysfunction and disorders normal hematological and biochemical profiles in addition to portal vein hypertension syndrome, ascites, and liver fibrosis. The general objective of the current study is to assess hematological and biochemical profiles of patients infected with Schistosoma mansoni in comparison with apparently healthy individuals (control group) in Sanja town, northwest Ethiopia. Method. A comparative cross-sectional study was conducted from February to April 2019 among microscopically confirmed S. mansoni-infected patients attending Sanja hospital and apparently healthy (control group) from Sanja town community. A total of 220 participants, 110 from the S. mansoni-infected and 110 from the control group, were enrolled using convenient sampling technique. Three grams of stool and six milliliters of blood samples were collected from each study participant. Stool samples were processed using the Kato–Katz technique to determine infection and count parasite density. The blood sample was processed for the analysis of hematological and biochemical profiles using Cell Dyn 1800 (Abbot Hematology, IL, USA) and iChem535 chemistry analyzer, respectively. All data were analyzed using SPSS version 20, and P value less than 0.05 was taken as statistically significant. Results. This study showed that the mean values of serum alanine aminotransferase, aspartate aminotransferase, total protein, total cholesterol, hemoglobin, mean corpuscular hemoglobin concentration, and total white blood cell count were different in the Schistosoma mansoni-positive group as compared with the control group with statistically significant value (P≤0.05). However, the mean values of blood glucose, red blood cell, packed cell volume, and granulocyte count difference were not statistically significant (P≥0.05). The mean value of hemoglobin, red blood cells, blood glucose, mean corpuscular hemoglobin concentration, total protein, total cholesterol, and total white blood cell was significantly dropped in the moderate and heavy S. mansoni parasitic load patients as compared with the control group and light S. mansoni parasite density patients. However, the mean of AST and ALT progressively elevated as the burden of S. mansoni increased. Conclusion. Most hematological and biochemical profiles were significantly lower in the Schistosoma mansoni-positive group as compared with the control group. Most hematological and biochemical profiles decline significantly as the parasite density increased. Hence, with Schistosoma treatment, supportive treatment against hematological and biochemical disorders is recommended.