Background and Objectives: Early childhood caries (ECC) is a multifactorial, biofilm-mediated, sugar-related, dynamic disease of primary dental hard tissues occurring in varying degrees of severity in infants and toddlers. Untreated ECC may lead to pain, infections, and severe systemic complications. The aim of this study was to systematically review and evaluate the scientific evidence on the cost-effectiveness of treatment decisions in ECC in infants and toddlers. Materials and Methods: Observational epidemiological studies, i.e., cohort studies, case–control studies, and randomized controlled trials, reporting cost-effectiveness of treatment decisions in ECC in infants and toddlers were included in the systematic review following the PRISMA guidelines. Using an ad hoc search with search terms or keywords (MeSH), electronic databases Embase, MEDLINE via PubMed, Scopus, and gray literature were searched. Results: The search identified 494 articles, of which 446 remained after removing duplicates. A total of 417 articles were excluded after title and abstract evaluation; 29 full-text articles were screened for eligibility, and five articles were discarded. Twenty-four full-text articles were included in the systematic review, assigning 17 to prevention and seven to restoration. Results were heterogeneous; comparability of included studies is difficult because of the different methodologies used. Conflicting efficacies were demonstrated for different interventions implemented, and cost-effectiveness data were documented. Conclusions: Socioeconomic, cultural, and ethnic differences must be considered when comparing conditions in terms of cost-effectiveness. A paradigm shift from surgical towards preventive treatment decisions can be observed. Cost-effectiveness studies on therapies for ECC in infants and toddlers are needed to identify the best practice approach and the most cost-effective therapy decisions.