Background <p>Adolescents with Autism Spectrum Disorder (ASD) face significant psychological and spiritual challenges that impact their overall quality of life. This study explores the psychological well-being (e.g., mood instability, financial burdens) of adolescents with ASD, including mental health challenges and coping mechanisms. We also studied the role of spirituality (e.g., participation in religious activities) as a coping mechanism for adolescents with ASD within the Ghanaian cultural context.</p> Methods <p>This qualitative study utilized semi-structured interviews with 13 parents of adolescents with ASD in Accra, Ghana. Participants were selected through purposive sampling. Data were analyzed thematically to identify patterns related to psychological well-being and spiritual practices as experienced by adolescents with ASD and their families.</p> Results <p>Two main themes emerged: (1) Psychological well-being of adolescents with autism, with parents reporting issues such as mood disturbances, depression, and social stigma affecting both adolescents and their families; and (2) Spiritual well-being, where religious engagement served as a coping resource, though sensory sensitivities posed participation challenges for some adolescents.</p> Conclusion <p>The study highlights the importance of accessible mental health resources and supportive spiritual communities for adolescents with ASD in Ghana. Community-based mental health services and inclusive spiritual support can help families address the psychological and spiritual needs of adolescents with autism more effectively.</p>