Background <p>Substance Use Disorders (SUDs) affect 5–6% of the global population, leading to substantial psychological and social burdens. Enhancing self-efficacy is central to recovery and relapse prevention, and life-skills training programs show promise in this regard. Yet, evidence from low-resource settings remains scarce.</p> Aim <p>This study aimed to evaluate the effect of life-skills training program on self-efficacy among patients with substance use disorders.</p> Method <p>A quasi-experimental one-group pretest-post-test design was used. A purposive sample of 45 male patients with Substance Use Disorders admitted in male addiction treatment and rehabilitation building at El Abbasia Mental Health Hospital )affiliated with the General Secretariat of Mental Health and Addiction Treatment (GSMHAT), Ministry of Health and Population, Cairo, Egypt( received a structured life-skills training program consisting of 15 group-sessions delivered twice weekly, focusing on behavioral, emotional, and wellness skills to enhance self-efficacy and prevent relapse. Self-efficacy was measured before and after the intervention using the Arabic version of the Alcohol Abstinence Self-Efficacy Scale (AASE). Data was analyzed using paired sample t-tests. Results: Patients showed a statistically significant improvement in overall self-efficacy scores following the intervention (t= -50.27, <i>p</i> &lt; 0.001), with notable improvement across all subscales including negative affect, social pressure, physical discomfort, and cravings.</p> Conclusions <p>Life skills training program had a positive effect on self-efficacy among patients with substance use disorders. Therefore, integrating life-skills training into rehabilitation and relapse prevention programs for patients with substance use disorders to enhance their capabilities and strengthen their self-efficacy.</p> Trial registration <p>ClinicalTrials.gov, NCT07174960. Retrospectively registered on 12 September 2025.</p>