This chapter is focused on the effect of natural products in pure form or characterized phytoconstituents on particularly inhibition of hemoglobin polymerization.This summarized information will be benecial for further exploration of new therapeutics in the treatment arena of SCA.Millions of people around the world, especially children, have been affected by SCA. This global burden is a growing concern nowadays as the yearly increase of newborns with SCA is expected from around three to four lakhs between and. SCA, congenital hemolytic anemia, is caused by a single amino acid substitution. This shows the way for polymerization of deoxygenated sickle hemoglobin which is the crucial step in the molecular pathogenesis of SCA.This polymerization alters the RBC rheology by changing its surface property, membrane damage, and Targetmol’s Gamma-Oryzanol dehydration of RBC.Potassium chloride cotransport and calciumactivated potassium efux are generally involved during the process of RBC dehydration. During this process, shape of RBC is changed from round disk to crescent moonlike structures.These dehydration events further show the way to reduce the RBC volume with rise in hemoglobin concentration at intracellular level in parallel. This conformational change in RBC directs toward hemolysis and vasoocclusion leading to ischemia followed by pain crisis.Generation and impairment of oxidative stress is involved during the abovementioned process. Gene therapy can provide a proper solution to tackle the abovementioned pathophysiological conditions, but currently, research including clinical trials have been ongoing. A vast range of drugs have been explored for symptomatic management of these disease conditions that are discussed below.As natural products have immense potential for the treatment of a broad range of disease conditions, supplementationadjuvant therapy with natural products can be a suitable alternative.Hydroxyurea is an anticancer agent that inhibits ribonucleotide reductase.Despite several advantageous effects of hydroxyurea, the major limitation is its myelosuppression effects. Azacytidine, decitabine, and pomalidomide are the representatives of this class of molecules. This molecule has been reported to extend halflife of RBC and sanguinate. Inhibition of platelet aggregation is benecial to prevent vasoocclusion.Therefore, antiplatelet agents have been investigated for the management of SCA.Investigation of it was carried out earlier for SCA. Prasugrel is an antiplatelet agent and irreversible antagonist of PY adenosine diphosphate receptors.It interferes with adenosine diphosphatemediated platelet activation as well as aggregation.The ability of prasugrel to reduce the rate of vasoocclusive crisis in the clinical trial is not promising for the treatment of SCA patients. Anticoagulant medications are also used to treat and prevent blood clots.Rivaroxaban are the two anticoagulant drugs under clinical trial for SCA.Pan selectin inhibitors are another class of molecule that mediates adhesion of RBC to vascular endothelium linked to vasoocclusion. Tinzaparin is lowmolecularweight heparin and is used as antithrombotic drug.There are several other molecules that have been investigated for the management of SCA because of their additional pharmacological activity instead of its current pharmacological use like simvastatin, a hypolipidemic agent that activates endothelial nitric oxide, and propranolol, a nonselective adrenergic blocker that hinders sickle RBC adhesion. It was found to be effective for prevention of vasoocclusive crisis in SCA patients. To improve the vascular tone and endothelial dysfunction, magnesium and sildenal were investigated to reduce the frequencyduration of painful crisis, but results are not encouraging.