Background: Diodia sarmentosa leaves have gained application in the local treatment of certain ailments. This study evaluated the effect of ethanol extracts of Diodia sarmentosa leaves on biochemical, antioxidant, and histopathological indices of monosodium glutamate-induced uterine leiomyoma in albino rats. Methods: Twenty-one (21) female adult albino rats were acclimatized for 10 days and then classified into three treatment groups, each containing seven rats. Group 1 was the normal control (NC) without any induction, Group 2 was the positive control (PC) and was induced with 200 mg/kg body weight of monosodium glutamate (MSG) without treatment, and Group 3 was the treated group (TG), induced with 200 mg/kg body weight of MSG, then treated with 400 mg/kg body weight of ethanol extract of Diodia sarmentosa leaves for 30 days. Results:The results of the study showed an impaired antioxidant system in the positive control (untreated group). Some biochemical parameters were also altered in the positive control, mostly revealing a relationship between uterine leiomyoma and renal impairment, or kidney damage. Treatment with ethanol extracts of Diodia sarmentosa leaves significantly (P < 0.05) improved the altered biochemical and antioxidant parameters. These findings were also supported by a histopathology result, which revealed the extent of tumors in the affected tissues. Conclusion: The ethanol extract of Diodia sarmentosa (Sw) leaves mitigated oxidative stress and improved the impaired antioxidant system caused by uterine leiomyoma induction.