Cyclophosphamide (CYL) is a first-line cancer chemotherapeutic agent widely used for the treatment of cancer that has severe toxic effects. The primary mechanism by which CYL induces toxicity through free radical generation. Morinda citrifolia (Noni) fruit juice is an herbal remedy documented to have antioxidant properties. The aim of the current study was to investigate the protective effect of noni against CYL-induced memory impairment in Swiss albino mice. Treatment schedule: Group 1: Normal: Received vehicle; Group 2: CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one; Group 3: NJ treatment: Received NJ (360 mg/b.w. p.o.) once daily for 14 days. Group 4: DNG treatment: DNG (360 mg/b.w. p.o.) once daily for 14 days, Group 5: NJ + CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one and after half an hour of received NJ (360 mg/b.w. p.o.) once daily for 14 days. Group 6: DNG + CYL treatment: Received CYL (40.0 mg/kg b.w. i.p.) on day one and after half an hour received DNG (360 mg/b.w. p.o.) once daily for 14 days. Mice were subjected to the Morris water maze (MWM) challenge for two weeks as part of a behavioral study. Short-term memory impairment was observed in the behavioral activity of CYL-treated mice in the MWM test in the 1st week trial, and this effect was reversed in the 2nd week trial in the combination treatment group. The behavioral analysis proved that noni supplementation reduced the risk of memory impairment caused by CYL. Biochemical analysis revealed that CYL markedly increased the levels of AChE and MDA in brain tissue. Similarly, decreases in the levels of antioxidants, i.e., GSH, CAT, SOD and GST, were detected in the brain tissue of the mice exposed to CYL. Qualitative and quantitative examinations of histopathological examination of the mouse hippocampus supported the above findings. The results demonstrated that noni supplement therapy reversed the changes in the MDA, AChE, and antioxidant enzyme levels while improving the behavioral and histological alterations caused by CYL. Long-term hippocampal growth and memory are unaffected, suggesting that CYL is less harmful. According to our research, supplementing with noni in conjunction with CYL may be a helpful treatment strategy for treating memory impairment caused by CYL.