Background: Trimethylamine N-Oxide (TMAO), as a gut microbiota-derived metabolite, has been associated with a number of chronic diseases like cardiovascular diseases. Objective: Considering the increasing prevalence of non-communicable diseases (NCDs), we conducted a systematic review to discuss the TMAO association with NCDs. Methods: A comprehensive search has been conducted on PubMed, Web of Science, and Scopus databases up to December, 2020. The inclusion criteria were all related observational studies that surveyed the association between TMAO levels and non-communicable diseases. Interventional studies, animal experiments, reviews, case reports, letters, congress abstracts, and studies that were not published in English were excluded. Moreover, related review studies were separately discussed. Results: Within 2191 recorded studies, 99 cross-sectional, case-control and cohort studies met the inclusion criteria. The most common diseases associated with TMAO levels are cardiovascular diseases, diabetes, kidney disease, stroke, inflammatory diseases, neurological disorders, and cancer. Elevated TMAO levels as a consequence of alteration in gut microbiota composition and dietary intake can lead to the incidence of NCDs. The high levels of TMAO can disrupt the homeostasis of glucose and lipids and induce inflammation that leads to serious NCDs. Conclusion: There is a dose-response relationship between TMAO levels and NCDs progression. Therefore, it can be studied as a therapeutic target or prognostic biomarker for dealing with NCDs.