Blood is a particular type of connective tissue that majorly contains red blood cells (RBCs), white blood cells (WBCs), and platelets (Plts). Anticoagulants are used to preserve the fluidity of blood and retard morphological changes in blood cells. Anticoagulants like EDTA, heparin, sodium citrate, and CPDA-1 are used. However, these anticoagulants also have some disadvantages, summarized in this review. This chemical causes the lysis of many cells, including RBCs, and some of them, like EDTA, cause agglutination of platelets, which not only causes a decrease in platelet count but also causes a spurious increase in WBC count. These substances also alter the shapes of various cells present in blood. RBCs and platelets may become spherical from the normal biconcave disc and plate-like structures. Commonly used anticoagulants contribute to alterations of many hematological parameters, including hematocrit, hemoglobin concentration, and packed cell volume of RBCs. Certain chemicals used in anticoagulant solutions, such as potassium and sodium in EDTA solution, make the blood unsuitable for determining these electrolytes in the sample. They also induce many changes in the biochemical composition of the sample. The most affected biochemical changes are observed in 2,3-DPG, D-dimer concentration, blood gas estimation, and cytokine levels. As they contain different chemicals, they have varying pH, so they alter blood pH.