Background: Nutrition is essential to life and can have an indisputable influence on health and prevention of disease development including cancer. Methyl-donors are macronutrients that are important in achieving a healthy balance of metabolic processes. Their deficiency can lead to several symptoms and diseases—even to severe SARS-CoV-2 infection. We aimed to explore the potential protective effect of methyl-donor intake in breast, colorectal and pancreatic cancer by patient follow up. Methods: A food frequency questionnaire and a diet diary were used to evaluate methyl-donor intake and blood samples were taken to evaluate Il-6 and IL-8 cytokine levels as well as MTHFR (C677T) polymorphism in breast, colorectal and pancreatic cancer patients. Results: We found that levels around the recommended daily intake of B6 and B9 were effective in supporting the overall survival of breast and colorectal, and a relatively higher level of pancreatic adenocarcinoma, patients. The total intake of methyl-donors significantly and negatively correlated with smoking in pancreatic cancer, while folate as well as betaine intake significantly and positively correlated with IL-8 in colorectal cancer patients. Conclusions: Our results suggest that the appropriate intake of methyl-donor can be an adjunct of conventional oncotherapy to improve quality of life. Whether methyl-donor intake supports cancer prevention and patient survival needs further confirmation in large patient cohorts.