The present study investigated the impact of aspartame (ASP) on biochemical and histological profiles and the therapeutic potential of aqueous extract of Phyllanthus niruri (PN) in female Swiss albino mice (20 ± 2 g b. w.). ASP (40 mg/kg b. w.) and PN (100 mg/kg b. w.) were fed to the mice for a period of 30 and 60 days. A significant (P ≤ .01) decrease was observed in body weight and relative organ weight in ASP-treated mice. ASP induced a significant (P ≤ .01) increase in lipid profile, bilirubin, creatinine, and enzyme activity. Furthermore, histomorphological changes in the liver and kidney, including atrophy, lesions, and derangement of cellular structure, were observed in ASP-treated animals. However, animals treated with ASP and supplemented with aqueous extract of PN showed significant (P ≤ .01) improvements in enzyme activity and histomorphological changes in the liver and kidney. Aqueous extract of PN mitigates ASP-induced physiological effects, including liver and kidney function markers and histomorphological changes. The study suggests a need for identification of mechanisms of interaction of ASP and its breakdown products once ingested and the bioactive compounds of PN responsible for its therapeutic potential.