The aim was to assess the associations between the LTF, MMP20, CA6, and TAS1R2 polymorphisms and caries in the Zhuang population and explore the underlying mechanism of the impact of lactoferrin on caries susceptibility. A case-control study of 315 adolescents was conducted in Guangxi, China, from May-November 2022. Data were collected through oral examinations and questionnaires. Buccal mucosa cells and DNA samples were collected using the SNPscan technique. Saliva and supragingival plaque samples were taken from 69 subjects with various LTF rs10865941 genotypes. The relationships among the LTF rs10865941 polymorphism, lactoferrin, Streptococcus mutans, and caries were investigated by using the ELISA and qRT-PCR, along with logistic regression analysis. The genotype distribution of the LTF gene were significantly different between the case and control groups (p = 0.018). The case group had lower C allele and greater T allele frequencies than the control group (p = 0.006). The LTF rs10865941 polymorphism was associated with caries in the codominant, dominant, and additive models (p < 0.05). MMP20 rs1784418, CA6 rs2274328, and TAS1R2 rs35874116 were not significantly different between the two groups (p > 0.05). A greater quantity of S. mutans. in the supragingival plaque was found in the case group (p = 0.03). There were significant differences between the two groups in both the codominant model and the dominant model (p < 0.05). The LTF rs10865941 polymorphism may be associated with caries susceptibility in the Zhuang population of China. The LTF rs10865941 T allele may be a potential risk factor for dental caries.