Abstract Background: Drepanocytosis (sickle cell anaemia) is a genetic disorder that causes stiff, rod-like sickle-shaped haemoglobin in red blood cells (RBCs) and consequently poses serious health complications. We investigated in vitro anti-sickling potential of a novel polyherbal formula (MPF). Methods: Sickling of RBCs induced with 2%sodium metabisulphite (MBS) was followed by treatment with MPF mixtures in different saline concentrations (7mg/ml, 9mg/ml, 14mg/ml and 28mg/ml). The red cell morphology was examined microscopically. Percentage sickling was quantified 30-minute interval at 370C for 2-hours. Effect of the MPF on membrane stability of RBCs was analyzed using osmotic fragility testing. Results: Qualitative phytochemical screening demonstrated the presence of some secondary metabolites namely; alkaloids, glycosides, phenols, saponin, tannin and terpenoids. Sickling of RBCs induced by MBS was inhibited by MPF. This antisickling effect was directly proportional to concentration of the MPF, dose-dependently. There was significant difference (P<0.05) between MPF-treated and untreated sickle cell counts. Osmotic fragility curves obtained from MPF-treated RBCs showed leftward shift against the untreated control indicative of increased membrane stabilization and/or haemolytic resistance. Conclusion: MPF demonstrated significant anti-sickling and erythrocyte membrane stability properties. These effects under hypoxia signify a promising effect of the bioactive components as probable drug candidates against sickling of red cells.