Background: This study aimed to investigate the mediating role of psychological distress (depression, anxiety, and stress) in the relationship between parental guilt and child's gender in mothers of children diagnosed with autism spectrum disorder and other neurodevelopmental disorders (NDDs). Methods: The study included 140 mother-child dyads, with children aged 36–72 months, 68 of whom were girls (48.6 %) and 72 were boys (51.4 %). NDD diagnoses were confirmed by a child and adolescent psychiatrist using a semi-structured clinical interview based on Diagnostic and Statistical Manual of Mental Disorders. Mothers completed a sociodemographic questionnaire, the Depression Anxiety Stress Scale (DASS-21), and the Guilt About Parenting Scale (GAPS). To examine the indirect effect of child gender on maternal psychological distress through maternal guilt, the mediation analyses and moderated mediation analysis were conducted using PROCESS macro for SPSS (Model 4 and Model 7). Results: Among the 140 children, 58 (41.4 %) were diagnosed with NDDs. The findings indicated that NDD diagnosis was significantly associated with higher anxiety levels. Additionally, maternal depression, anxiety, and stress were linked to higher levels of parental guilt. Moderated mediation analysis showed that depression and anxiety mediated, but stress did not, the relationship between NDD diagnosis and parental guilt in mothers of female children, whereas no such effect was found in mothers of male children. Conclusion: These findings highlight the importance of assessing maternal anxiety and depression—especially in mothers of female children—when evaluating parental guilt in families of children with NDDs. A comprehensive and holistic approach may contribute to better psychological support for these mothers.