We aimed to assess the impact of malocclusion on oral health-related quality of life (OHRQoL) in a sample composed of adolescents, younger adults and adults seeking orthodontic treatment. Participants were consecutively enrolled from January 2019 to March 2020. The oral health impact profile (OHIP-14) was used to measure the OHRQoL. The index of complexity, outcome and need (ICON) was used to assess malocclusion. Sociodemographic, medical, and clinical questionnaires were recorded. Statistical analyses were performed according as a function of sex and age range (15–30 or >30 years old). Linear and logistic regression models were applied to assess the association between OHIP-14 total score, malocclusion, and other relevant confounding variables. In a final sample of 93 participants (60 females and 33 males, aged 15 to 60 years), men reported significantly better OHRQoL (p = 0.005). Participants aged 30 years or older reported significantly worse OHRQoL (p = 0.042). OHIP-14 was significantly correlated with age (ρ = 0.259, p < 0.05) and the number of missing teeth (ρ = 0.369, p < 0.001). Multivariable regression showed OHIP-14 being associated with the number of missing teeth (B = 1.48, SE = 0.57, p < 0.05) and the presence of missing teeth (B = 1.38, SE = 0.65, p < 0.05). Malocclusion showed no association with OHRQoL. Age and the number of missing teeth may be key factors on self-perceived OHRQoL in adult patients seeking orthodontic treatment.