The aim was to compare two strategies for caries prevention in children with Autism Spectrum Disorders (ASDs). Participants were retrospectively retrieved and divided in two groups. Group one had first permanent molars treated with fluoride varnishes, FA group (n = 92, 9.43 ± 2.44 years) whilst the second, with dental sealant plus fluoride varnishes, FA + S group (n = 140, 7.77 ± 2.57 years). Logistic and multivariate analysis were run to evaluate the caries incidence, the retention rate of sealants, and background factors associated with caries risk over a period of at least 11 years. Survival rates from dental caries were statistically significantly higher in the FA + S group compared to the FA group (LogRank test p < 0.01). Dental sealant plus fluoride varnish played as a protective factor towards the development of caries (HR = 0.25 CI = 0.00/0.55 and HR = 0.34 CI = 0.00/0.66 in the upper right and left first molars; HR = 0.32 CI = 0.00/0.66 and HR = 0.26 CI = 0.00/0.58 in the lower right and left first molars). Dental sealants retention rate was high, ranging between 58.02% and 64.29%. No baseline variable was statistically significantly associated to the risk of caries development. Combined dental sealant and fluoride varnish application was more effective in reducing caries risk in first permanent molars of ASDs children than fluoride varnish alone. This preventive strategy should be therefore routinely applied in high caries risk patients as ASDs children.