Background: Family-centered empowerment of drug and stimulant users is an effective program for a better response to treatment, prevention of treatment adverse effects, and promotion quality of life (QoL) and lifestyle in the process of discontinuing drug abuse.Objectives: This study aimed to determine the effects of educational intervention, based on family-centered empowerment and Pender's health promotion models, on health-promoting lifestyle and health-related QoL among methamphetamine users and their families.Patients and Methods: In a randomized clinical trial, methamphetamine users, who were admitted to Tehran University of Medical Sciences Substance Abuse Treatment Centers, were randomly allocated to three groups: a group for training of methamphetamine users who were in recovery phase (intervention group 1; 95 subjects); a group for training of a family member of methamphetamine users who were in recovery phase (intervention group 2; 95 subjects); and a control group (95 subjects). A demographic checklist and a standard questionnaire covering health-promoting lifestyle, health-related QoL, self-efficacy, perceived affect, perceived social support, and perceived barriers dimensions were used to gather required data. Independent-samples t test, paired-samples t-test, and ANCOVA were used to analyze the data.Results: Analysis of covariance showed that after adjusting for effects of pretest scores, the difference between mean post-test scores of health-promoting lifestyle scale, health-related QoL scale, and all constructs of Pender's health promotion model (self-efficacy, perceived affect, perceived social support, and perceived barriers) in the intervention group 1 and control group were significant (P<0.0001). In addition, changes in mean scores of lifestyle scale (42.4±13.6), QoL scale (29.1±14.2), self-efficacy (16.1±2.6), perceived affect (16.1±8), social support (35.4±12.4), and barriers (17.2±15.8) before and after intervention were significant in the intervention group 2 (P<0.0001).Conclusions: Application of family-centered empowerment model among methamphetamine users and their families is practically feasible and can result in enhancement and improvement of their QoL, lifestyle, and health promotion model constructs.