Objective: Autism spectrum disorder (ASD) is characterized by deficits in social interaction, communication, restricted interests, and repetitive patterns of behavior. This study examined quality of life (QoL) and related clinical factors in children with ASD, compared to children with Attention Deficit Hyperactivity Disorder (ADHD), children with asthma, and healthy controls (HC). Methods: QoL was assessed by the Pediatric Quality of Life Inventory 4.0 (PedsQLTM 4.0). Additionally, parents of the children provided sociodemographic information and filled out an evaluation questionnaire, child behavior check list (CBCL), and Turgay DSM-IV Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S). Results: The physical health, psychosocial health, social functioning, and scale total score of the ASD group were significantly lower than those of the three comparison groups. The school functioning score domain was lower in the ASD group than in the asthma and HC groups. In contrast, the emotional functioning domain assessments did not reveal statistically significant differences between the ASD group and the comparison groups. In the ASD group, the total problem score, inattention, and hyperactivity scores were significantly higher than both the asthma and HC groups, and the internalizing scores were higher than the healthy group. Conclusion: The poor QoL is most likely due to functional losses and problem behaviors related to ASD and may negatively affect not only children with ASD but also the whole life of the family.