Purpose: The purpose of this systematic review and meta-analysis was to assess the impact of dental caries on the oral health-related quality of life (OHRQoL) of preschool children. Methods: A literature search was undertaken through PubMed/MEDLINE, Scopus, and TRIP databases to verify available studies about the topic. Two reviewers independently selected the studies, extracted the data, and assessed the bias risk. Global meta-analysis was carried out comparing means and standard deviations of the OHRQoL overall score from preschool children with and without caries. Subgroup analysis was conducted using different cutoff points for caries: decayed, missing, or filled teeth (dmft) greater than or equal to one and greater than or equal to six. Results: From 597 potentially eligible studies, 63 were selected for full-text analysis and 29 were included in the review: 12 for quantitative analysis and 17 for qualitative analysis. Most studies were conducted in Brazil; Early Childhood Oral Health Impact Scale (ECOHIS) was the instrument used in most studies to evaluate OHRQoL. A dmft index at least of one was sufficient to negatively impact the OHRQoL of preschool children, although a higher cutoff point for caries augmented the difference between groups. Bias risk was low. Conclusions: Caries might be associated with negative impact on the oral health-related quality of life of preschool children, and this association tends to increase as the disease severity worsens.