Medicinal plants have been shown to affect the stability of the erythrocyte membrane. Dissotis rotundifolia leaves have been used in Nigeria to treat certain diseased conditions not minding the effect on the erythrocyte membrane. The aimed of this work is to investigate the impact ethanolic extract of Dissotis rotundifolia leaves have on wistar rat erythrocyte membrane. Twenty-five adult wistar albino rats were randomly distributed into five groups administered 0 (control), 50, 100, 150 and 200 mg/100 g body weight. Erythrocytes osmotic fragility was determined by measuring the release of haemoglobin from blood added to tubes containing serially diluted phosphate buffered saline (PBS, pH 7.4). The results of mean corpuscular fragility (MCF) showed non-significant (p > 0.05) decrease for 50 and 100 mg/100 g body weight doses, while 150 and 200 mg/100 g body weight doses showed non-significant (p > 0.05) increase. The erythrocytes were stabilized by 50, 100 and 150 mg/100 g body weight, while 200 mg/100 g body weight destabilized the erythrocyte membrane. Also, 200 mg/100 g body weight dose showed significant (p ≤ 0.05) increase in malondialdehyde (MDA) levels. At relatively high doses, Dissotis rotundifolia may induce oxidative stress causing significant levels of MDA production resulting in alteration of the chemical and structural composition of the membrane. In conclusion Dissotis rotundifolia at low doses may be useful in maintaining the erythrocyte by stabilizing the membrane, whereas high doses destabilize the membrane and compromise membrane integrity.