INTRODUCTION: Opioid use disorder (OUD) is a prevalent problem among Egyptian youth, and achieving recovery and abstinence is challenging. Cognitive behavioural therapy (CBT), a well-known approach, can be particularly beneficial when it addresses psychological aspects such as resilience, self-esteem and spirituality. This study aimed to evaluate the effectiveness of a spiritual adaptation of CBT in enhancing these factors among clients with OUD. A quasi-experimental study with a control group was conducted using a pretest-posttest design. The study included 49 clients with OUD and 46 clients in the control group. The Rosenberg Self-Esteem Scale-Modified Arabic Version, Daily Spiritual Experience Scale, and the Connor-Davidson Resilience Scale were used as measurement tools. CBT was delivered in 60-min group sessions. After 3 months, the questionnaires were re-administered to evaluate the effectiveness of a spiritual adaptation of CBT sessions. The study found a statistically significant increase in the mean scores of resilience, self-esteem and spirituality (p < .001 each) following a spiritual adaptation of CBT sessions compared to the control group. A spiritual adaptation of CBT effectively enhanced resilience, self-esteem and spirituality in clients with OUD. Understanding the effectiveness of a spiritual adaptation of CBT in enhancing resilience, self-esteem and spirituality can enable psychiatrists and nurses to provide more comprehensive and effective care to patients with OUD.