Despite governmental regulations on the use of anti-malarial, antibiotic, and analgesic medications, reports indicate a rise in their misuse. This study evaluated the effects of artemether-lumefantrine (AL), ciprofloxacin (CPX), and diclofenac (DFC) on oxidative stress markers in female Wistar rats. 96 female Wistar rats were divided into 8 groups of 12. Group 1 served as control, while groups 2-8 were administered AL, CPX, DFC, AL+CPX, AL+DFC, CPX+DFC, and AL+CPX+DFC, respectively. Doses were 178 mg/kg for AL, 185 mg/kg for CPX, and 9 mg/kg for DFC. After oral administration for 6 and 12 weeks, blood and tissues (liver, kidney, heart, spleen, and small intestine) were collected for biochemical and histological analysis. Oxidative stress markers {nitric oxide, thiols, catalase, superoxide dismutase, paraoxonase, protein carbonyl, malondialdehyde, and oxidized low density lipoprotein cholesterol (oxLDL-C)}, were assessed in the serum and tissues. Data was analysed using GraphPad Prism 5, with one-way ANOVA at a 5% significance level. Results showed significant increases (p?0.05) in protein carbonyl, oxLDL-C, nitric oxide, catalase, superoxide dismutase, and paraoxonase across the treatment groups at week 6 and 12. Group 8 exhibited marked reduction (p?0.05) in glutathione levels and catalase activity at week 6 and 12, respectively. Histological analyses revealed tissue alterations in the liver, kidney, heart, spleen, and small intestine in all treatment groups at week 6 and 12. Co-administration of AL, CPX, and DFC disrupted the oxidative balance, leading to dysfunctions in the liver, kidney, spleen, heart, and small intestine. Consequently, the indiscriminate use of these drug combinations should be avoided.