Fermented papaya preparation (FPP) is a “natural health product.” The high incidence of dental caries, gingivitis, periodontitis, and oral microbial infection cases among patients with diabetes mellitus continues to prevail. The potential role of FPP against common oral microbiota (Streptococcus mutans, Streptococcus mitis, and Lactobacillus acidophilus) isolated from the human oral cavity was investigated using in vitro simulation models of dental plaque and caries. FPP showed an inhibitory effect against the growth (at 0.05 mg/mL: S. mutans: −6.9%; S. mitis: −4.47%, P < 0.05), acid production (at 0.05 mg/mL: S. mutans: +6.38%; L. acidophilus: +2.25%), and hydrophobicity (at 50 mg/mL: S. mutans: 1.01%, P < 0.01; S. mitis: 7.66%, P < 0.05) of tested microbiota. The results of this study suggest that low doses of FPP may be a suitable complement to good oral hygiene practice for the effective prevention of dental caries, plaque, and gingivitis. The functional application of FPP as a constituent of a balanced diet and active lifestyle can make a positive contribution to the oral health status and well-being of patients with diabetes.