Background: Children are the most sensitive and vulnerable group in terms of tooth decay. Any change or improvement in health-related knowledge and behavior in this group can have long-term and significant impacts on the health of the future generation. Thus, the present study was conducted with the aim to determine the relationship of knowledge of oral health-related issues with the decayed, missing, and filled teeth (DMFT) index in 12-year-old students of Rafsanjan, Iran, in 2016. Materials and Methods: This descriptive, cross-sectional study was performed on 460 students (230 boys and 230 girls) of 12 years of age from 10 elementary schools in Rafsanjan. The subjects were randomly selected. Data were collected through clinical examination, interviews, and a questionnaire. The questionnaire consisted of two parts; the first part contained a demographic characteristics form, and the second part contained the DMFT index and questions on knowledge of oral health-related issues. Data were analyzed using independent t-test, ANOVA, chi-square, and the Pearson correlation coefficient (α = 0.05). Results: Mean DMFT index and knowledge score of the students were 2.66 ± 1.40 and 5.43 ± 1.82, respectively. Students with higher knowledge had lower DMFT index. Moreover, mean knowledge score of students with homemaker mothers was significantly higher compared to students with working mothers. Conclusion: The results of this study suggested a positive significant relationship between knowledge of oral health-related issues and DMFT index in 12-year-old students of Rafsanjan.