Background: Sickle cell disease is a genetic disorder in which an individual inherits the sickle cell allele from both parents. The modern disease modifying therapies are quite expensive and often come with side effects, hence, there is need to search for natural alternatives from medicinal plants. This research was aimed at evaluating the antisickling effects of some selected medicinal plants. Materials and Methods: Ethnobotanical survey was conducted on the medicinal plants used in Zuru Local Government Area of Kebbi State, Nigeria for the treatment/management of sickle cell disease. Five (5) most cited plants; Carica papaya leaf, Prosopis africana stem-bark, Guiera senegalensis leaf, Syzygium aromaticum seed and Boswellia dalzielli stem bark were selected and their methanol extracts were subjected to in vitro antisickling activity using sodium metabisulphite. Phytochemical screening on the most active plant extracts was conducted using standard methods. Results: The plant extracts and their combinations exhibited antisickling activities with varying degrees of efficacy. C. papaya leaf extract, P. africana stem bark extract and G. senegalensis leaf extract were the most potent that caused reduction in the percentage sickling to 3.87±2.73, 8.38±1.06 and 28.35±2.07% respectively. Phytochemical screening revealed the presence of alkaloids and Tannins in all the three (3) plant extracts. Anthraquinones and glycosides were present only C. papaya and G. senegalensis leaf extracts, while Flavonoids and Saponins were only present in G. senegalensis leaf extract and P. africana stem bark extracts. Phenols were present in C. papaya leaf extract and P. africana stem bark extracts, while phlobatannins was only in C. papaya leaf extract. Conclusion: The medicinal plant extracts were able to reduce the percentage of sickled cells. This may be due to the presence of some of the phytochemicals. Hence, these medicinal plants may be used as alternative to hydroxyurea in ameliorating the sickling in human HbS containing RBCs.