The aim of the present study was to assess the impact of malocclusion on oral health-related quality of life (OHRQoL) among preschool children and their families. This study involved 732 preschoolers. Parents/caregivers filled out the Brazilian version of the Early Childhood Oral Health Impact Scale (B-ECOHIS) and a questionnaire addressing sociodemographic data. Overbite, overjet, and crossbite were recorded during the clinical examination. Bivariate and multiple Poisson regression analyses were performed and prevalence ratio (PR) were calculated (α = 5%). The prevalence of negative impact from malocclusion on OHRQoL was 27.6% among the children and 22.3% among the families. Mother's schooling (PR = 1.37; 95% CI: 1.10–1.70), parent's/caregiver's assessment of child's oral health (PR = 2.07; 95% CI: 1.60–2.58), history of toothache (PR = 3.84; 95% CI: 2.34–6.30), and visits to the dentist (PR = 0.59; 95% CI: 0.37–0.94) remained significantly associated with OHRQoL in the final model for the children, whereas parent's/caregiver's assessment of child's oral health (PR = 2.32; 95% CI: 1.71–3.14) and history of toothache (PR = 2.28; 95% CI: 1.69–3.09) remained significantly associated with OHRQoL for the families. Malocclusion was not associated with a negative impact on OHRQoL. In contrast, parents’/caregivers’ perceptions regarding the oral health of their children and a history of toothache were predictors of a negative impact on the OHRQoL.