<p>This study is conducted to investigate and contrast the effect of pyridoxine and ascorbic acid on mild cognitive impairment and quality of life in post-menopausal women. A randomized, controlled trial was carried out involving post-menopausal women with mild cognitive impairment. A total of 180 eligible participants were randomized to group A (25&#xa0;mg of pyridoxine), group B (100&#xa0;mg of ascorbic acid), and group C (not receiving any drug). The intervention time was 6&#xa0;months. The Montreal cognitive assessment (MoCA) scale was utilized to assess cognitive function. Serum beta-amyloid (Aβ) 42 and homocysteine (Hcy) levels were measured. We used the menopause-specific quality of life (MENQOL) questionnaire to evaluate the quality of life (QOL) of post-menopausal women. Both pyridoxine and ascorbic acid have improved total MoCA scores (<i>p</i> = 0.0323 and <i>p</i> = 0.0074) compared to baseline. The Hcy level was reduced significantly in pyridoxine than in ascorbic acid (<i>p</i> = 0.0060). The serum Aβ 42 decreased significantly with pyridoxine and ascorbic acid (<i>p</i> = 0.0311 and <i>p</i> = 0.0042). In the MENQOL score, ascorbic acid has significantly reduced the score of the physical domain (<i>p</i> = 0.0020). However, a significant reduction in the overall score of MENQOL was not noticed before and after the treatment of pyridoxine and ascorbic acid (<i>p</i> = 0.3724 and <i>p</i> = 0.0732). Pyridoxine is more effective than ascorbic acid in lowering Hcy levels among post-menopausal women. Pyridoxine and ascorbic acid have been shown to improve cognitive function, and further long-term research is imperative to validate these findings. The trial was registered in the Clinical Trial Registry of India and registration no. is CTRI/2023/03/051131. Registered on: 28/03/2023—trial registered prospectively.</p>