A worldwide increase in waterpipe consumption can be observed. The present systematic review aims to assess cytotoxic and genotoxic impacts on oral health related to waterpipe smoking. We searched MEDLINE, Cochrane Library, and Dimensions evaluating if waterpipe smokers (P) have any cytotoxic or genotoxic effects on oral cells (I) compared to non-smokers (C) regarding mouth neoplasms (O). PRISMA guidelines were adopted for the current systematic review. Review Manager was utilized for statistical analysis (p < 0.05). A risk of bias and summary were performed to assess the grade of the 20 included articles. With some of the articles included, a forest plot was created in different levels. Waterpipe smoking is harmful to oral health, causing cytotoxic and genotoxic effects on oral cells with a Risk Difference of 0.16. It causes a series of detrimental cellular and genetic modifications such as acanthosis, epithelial dysplasia, and hyperparakeratosis. Changes in DNA methylation and p53 expression were assessed among others. In addition, waterpipe has a bunch of carcinogenic compounds. Even with few publications on the subject, articles are very devastating in confirming the carcinogenicity of waterpipe smoking. Waterpipe smoke is cytotoxic and genotoxic. Due to the release of many organic compounds, it increases the incidence of oral cancer.Keywords: Mouth Neoplasms; Oral Health; Smoking Water Pipes; Tobacco Use; Toxicity Measure.