Background/Objectives: Dental caries remains one of the most prevalent chronic diseases in early childhood, and traditional preventive strategies often fail to achieve sustained risk reduction without individualized management. The Caries Management by Risk Assessment protocol (CAMBRA) provides a structured, risk-based preventive approach integrating clinical and behavioral indicators. This study evaluated the two-year effectiveness of a CAMBRA-based prevention program in preschool children. Methods: A prospective observational cohort study was conducted in a university-affiliated pediatric dentistry clinic in Italy. A total of 296 children aged 4–6 years were enrolled and classified into caries risk categories according to CAMBRA criteria. Personalized preventive plans included oral hygiene education, dietary counselling, fluoride applications, and sealants where indicated. Clinical outcomes were assessed over a 24-month follow-up period. Results: Over two years, a substantial shift toward lower caries risk categories was observed, with the proportion of children classified as High/ Very High risk markedly reduced. Improvements were also recorded in caries experience (dmft) and oral hygiene status (OHI-S). Greater adherence to scheduled follow-up visits was associated with a higher likelihood of clinical improvement. Conclusions: A CAMBRA-based, risk-guided preventive program implemented in a public pediatric dental setting was associated with meaningful improvements in caries risk profiles and oral health parameters over 24 months. Regular follow-up and caregiver engagement appear to be key factors in sustaining preventive benefits in high-risk preschool populations.