Abstract Background and Objectives Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive functions and its initial symptoms are easily mistaken for stress or ageing. The current study was conducted to throw light on the effect of metformin, solely and in combination with vitamin B12, on LPS –induced AD like neurodegeneration and to elucidate the underlying mechanisms in non diabetic rats. Methods 35 adult albino male rats, were randomly allocated into the following groups: Group I: Control rat group (C), Group II: LPS- induced Alzheimer group (LPS), Group III: LPS-induced Alzheimer’s disease group supplemented with metformin: (LPS-Metformin), Group IV: LPS- induced Alzheimer’s disease group supplemented with metformin & Vitamin B12: (LPS- Metformin & vit B12). Behavioral assessment tests were done. At the end of the study, serum glucose, insulin, and plasma vit B12, malondialdehyde (MDA), glutathione peroxidase (GPX), tumor necrosis factor α (TNF α), and interleukin-6 (IL-6) levels were assessed. Histopathological examination of the brain tissue was also performed. Results The results of behavioral tests revealed that the time consumed by the animal for reaching the platform at the water maze test was significantly prolonged, while the time stability values by the animal at low and high velocities at rotarod test were significantly decreased in the LPS group compared to the control group. The biochemical results revealed that serum glucose and insulin, as well as HOMA-IR values, were significantly increased while plasma vit B12 was significantly decreased in the LPS group compared to the control group. Upon treatment with metformin solely or in combination with vitamin B12, these changes were improved. These results were further confirmed by histopathological examinations. Conclusion Metformin had a prophylactic effect on LPS induced neurodegenerative disease like dementia as it enhanced cognitive function, however it did not change locomotor and balance performance. This was explained, partially by its anti-inflammatory and anti-oxidant effects.