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. 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. 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. 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.