The increased prevalence and mortality of sickle cell disease necessitates more research on its management and treatment. This study investigated the antisickling potential of Auricularia auricula obtained from its natural environment within the University of Port Harcourt in Nigeria. Freshly harvested mushrooms were washed, air-dried, and ground and distilled water was added. The mixture was divided into two parts; one part was extracted by cold maceration and lyophilized to give cold maceration extract, while the filtrate obtained after boiling and cooling of the second part was dried in an autodesiccator to give decoction extract. Volumes of both extracts were obtained via serial dilution. Sickle cell hemoglobin S (HbS) erythrocytes were obtained by centrifuging HbS-blood in 0.9% physiological saline. The percentage of lysis decreased when 10 and 5 mg/mL of both extracts were added to erythrocytes suspended in hypotonic buffered saline, while the lowest median corpuscular fragility was observed for cold maceration extract at 5 mg/mL. The lowest negative percentage of stability and highest morphological stability were observed for decoction extract at 10 and 5 mg/mL after 5 min of culturing in decoction extract, respectively. The ability of A. auricula extracts (mainly the decoction extract) to reverse and stabilize erythrocyte membrane integrity and morphology is a clear indication that this mushroom may offer a valuable natural option for the treatment and management of sickle cell anemia.