Evidence of the effects of water-soluble vitamins (e.g., B vitamins, vitamin C, and total folate) on cognitive function in patients with neurodegenerative diseases is mixed. Furthermore, the relationships among homocysteine (Hcy) metabolism, water-soluble vitamins, and cognitive impairment remain unclear. Therefore, we aimed to investigate the role of the levels of water-soluble vitamins [e.g., vitamins B1, B2, B3, B5, B6, 5-methyltetrahydrofolate (5mTHF), B12, and C and total folate] and Hcy in dementia progression in patients with neurodegenerative diseases. In this retrospective cohort study, we enrolled 280 healthy controls and 646 patients with a neurodegenerative disease. Patients were classified into a Parkinson's disease (PD) group (n = 312), Alzheimer's disease (AD) group (n = 219), or other dementia group (n = 115) according to pathological features. The other dementia group comprised 25 patients with frontotemporal dementia, 38 with Lewy body dementia, 34 with vascular dementia, and 18 with semantic dementia. Serum vitamins (i.e., B1, B2, B3, B5, VB6, 5mTHF, and C) were measured via liquid chromatography-mass spectrometry/mass spectrometry. Total Hcy, vitamin B12 and total folate levels were measured using commercial electrochemiluminescence immunoassays. The serum levels of vitamins B1, B2, B5, B6, 5mTHF, and C were lower in all patient groups than in the control group. The logistic regression results revealed that lower levels of serum vitamins B2, B6, 5mTHF, and B12 were associated with a higher risk of dementia in PD patients, and higher Hcy levels and lower serum vitamin B6 and 5mTHF levels were associated with a higher risk of AD-related cognitive impairment. In addition, the level of vitamins was positively correlated with neuropsychological assessment scores and negatively correlated with Hcy level and stage of dementia. The levels of several water-soluble vitamins are lower in dementia patients. Moreover, lower levels of water-soluble vitamins and higher levels of Hcy increased odds ratios for having neurodegenerative diseases or cognitive impairment. These findings suggest that estimating water-soluble vitamin levels in older adults may be valuable given that they may help improve cognitive function.