There is a lack of evidence of the moderating effects of caries lesions and malocclusions on oral health-related quality of life (OHRQoL) among older adolescents. This study aimed to evaluate the relationship of dental caries and malocclusion with OHRQoL among Lithuanian adolescents aged 15 to 18 years. A survey in a representative sample of adolescents included a clinical examination to assess dental health status using the DMFT (Decayed, Missing, and Filled Permanent Teeth) index, and malocclusion using the Index of Complexity, Outcome, and Need (ICON). The Child Perceptions Questionnaire (CPQ) was used to evaluate respondents’ OHRQoL. Negative binomial regression was fitted to associate the clinical variables with the CPQ scores. A total of 600 adolescents were examined. The overall mean DMFT score was 2.7. A need for orthodontic treatment was detected among 27.7% of adolescents. Subjects with caries lesions (DMFT > 3) had higher CPQ scores in the domains of functional limitations and social wellbeing (relative risks were 1.35 (95% confidence interval: 1.09–1.67) and 1.30 (1.03–1.64), respectively), while subjects with a need for orthodontic treatment (ICON > 43) had higher CPQ scores in the domains of emotional wellbeing and social wellbeing (relative risks were 1.81 (1.40–2.22), and 1.69 (1.34–2.14), respectively). It was concluded that both dental caries and malocclusion have negative relationships with OHRQoL in adolescents above 15 years, but their effects occur differently in each OHRQoL domain.