Background: Fluorides are an essential component of oral hygiene products used to prevent dental decay. Therefore, a question arises about the potential harms of joint use of fluoridated toothpaste and mouthwashes regarding the increased amount of fluoride in the oral mucosa. Methods: This prospective, double-blinded parallel randomized clinical trial was conducted using a buccal micronucleus cytome assay (BMCyt assay). Forty-one participants were randomly assigned to the two groups. All participants used the same kinds of toothpaste for 12 weeks, designed explicitly for this study (non-fluoride, 1050 ppm F, and 1450 ppm F each for 4 weeks). Simultaneously, during the 3 months of the research, one group used mouthwash with fluoride (450 ppm) and another without fluoride. The buccal mucosal sampling was taken before using the tested products and after 4, 8, and 12 weeks of their use. Results: The frequency of micronuclei and the majority of other scored endpoints from the BMCyt assay showed no statistically significant differences within and between the studied groups. Comparing two groups, only statistically significant increases in the number of cells with nuclear buds (p = 0.048) and karyorrhexis (p = 0.020) at four weeks of usage were observed in the group that used mouthwash with fluoride. Conclusion: On the basis of the results, it can be concluded that simultaneous application of fluoridated toothpaste and fluoride mouthwash does not lead to cytogenetic damage in buccal mucosal cells.