The study aimed to evaluate the effectiveness of sustained interventions in children with cleft lip and palate (CLP) for preventing early childhood caries (ECC). This prospective, nonrandomized interventional cohort study was conducted in infants aged 0-12 months with congenital CLP. Interventions were given to parents/primary caregivers in the form of combined oral health-care measures (sterile wet gauze piece, finger brush, toothbrush, and toothpaste) by a motivational interviewing approach. Education of primary caregivers on oral hygiene was provided by audiovisual aids and demonstration. Reinforcement of the prescribed regimen was done through daily short message services in caregivers' preferred language and bimonthly telephone calls. Participants were followed up for 9-32 months from the time of recruitment, with a mean period of 18.3 ± 5.1 months. Rates of dental caries were represented as prevalence rates, incidence density, and transitional probability. The distribution of the International Caries Detection and Assessment System (ICDAS) scores on different tooth surfaces affected in the intervention group was compared descriptively with that of the age- and sex-matched historical control groups. On analysis of surface-wise distribution of the ICDAS scores in the intervention group (n = 1,919), 1.2% (n = 24) had noncavitated lesions (ICDAS codes 1 and 2), 0.88% (n = 17) had cavitated lesions (ICDAS codes 3-6), and 0.26% (n = 5) had both cavitated and noncavitated lesions (ICDAS codes 1-6). The incidence density of caries-affected children observed at the first and last follow-ups was 1.2 persons/100 person-months and 1.3 persons/100 person-months of observation, respectively. The incidence density of new caries-affected tooth surfaces at the first and last follow-ups was 0.163 surfaces/100 surface-months and 0.062 surfaces/100 surface-months, respectively. Maxillary first molars had the maximum transition from sound to the cavitated lesion (11.5%), followed by maxillary incisors from sound to noncavitated (7.5%) at the last follow-up. Based on the newly developed assessment criteria in our study, sustained interventions proved to be significantly effective in preventing ECC in children with CLP.