The aim of this research was to compare the mental health of families with children diagnosed with autism spectrum disorder or typically developing children, during the first and the second wave of COVID-19 outbreak in Slovakia. The study is mainly focused on the prevalence of depression, anxiety, and stress among the parents and maladaptive behavior or sleep disturbances of their children. Our research sample consisted of 332 caregivers, 155 of which have children with autism spectrum disorder; 179 surveyed during the first wave and 153 during the second wave. Extensive online parent questionnaire was created, including demographic and specific topic–related questions; Depression, Anxiety, and Stress Scale–42 questionnaire; and two subscales of Vineland Adaptive Behavior Scales—internalizing and externalizing maladaptive behavior. During the first wave, high levels of anxiety were found in parents of autism spectrum disorder children. During the second wave, all parents experienced increased levels of anxiety, stress, and depression, but especially severe for parents of children with autism spectrum disorder. Internalizing maladaptive behavior of children with autism spectrum disorder grew significantly between the waves. Parental depression, anxiety, and stress positively correlated with maladaptive behavior in both autism spectrum disorder and neurotypical children, suggesting a need for therapy options for whole families. Lay abstract A global pandemic caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2) affected everyday lives of all people, including individuals with special needs, such as autism spectrum disorder. The aim of this research was to compare the mental health of families with children with autism spectrum disorder to families with typically developing children, and between the first and the second wave of COVID-19 outbreak in Slovakia. This mainly included symptoms of depression, anxiety, and stress of parents and problem behavior or sleeping difficulties of their children. The research sample consisted of 332 parents (155 of which have children with autism spectrum disorder), 179 surveyed during the first wave and 153 during the second wave. Online parent questionnaire was created, including demographic and specific topic questions, Depression Anxiety and Stress Scale–42 questionnaire, and internalizing and externalizing maladaptive behavior subscales from Vineland Adaptive Behavior Scales. Our results show that during the first wave, parents of autism spectrum disorder children suffered high levels of anxiety. During the second wave, both groups of parents suffered increased anxiety, stress, and depression, but especially severe for parents of children with autism spectrum disorder. Internalizing maladaptive behavior of autistic children grew significantly between the waves. Parental depression, anxiety, and stress were interconnected with maladaptive behavior of both autism spectrum disorder and typically developing children, suggesting the importance of the therapy options for whole families.