Background Little evidence has examined the therapeutic effects of methylphenidate (MPH) and Matrix Model treatment on addiction severity, craving, relapse and mental health in people who use methamphetamine (PWUM). This study was conducted to determine the effects of MPH, Matrix Model treatment, and Matrix-MPH on addiction severity, craving, relapse and mental health in PWUM. Methods This clinical trial was conducted among 100 patients with METH users. Participants were randomly divided into four groups who received: 1) 22 sessions of 45-min, twice a week for Matrix Model treatment (n = 25); 2) MPH 10 mg/day in the first month, 7.5 mg/day in the second month and 5 mg/day in the third month (n = 25); 3) Matrix Model treatment combined with MPH (n = 25); 4) control group (n = 25) for 12 weeks. Addiction severity, craving, relapse and mental status were evaluated at baseline and end-of-trial. Results Matrix Model treatment combined with MPH significantly reduced MA craving (P < 0.001) and addiction severity (P < 0.001). In addition, Matrix Model treatment combined with MPH resulted in a significant increase of mental health (P = 0.001), compared with Matrix Model treatment, MPH, and control group. Also, negative METH urine test significantly increased in the Matrix Model treatment combined with MPH group compared with the other groups (P < 0.001). Conclusions In conclusion, Matrix Model treatment combined with MPH for 12 weeks had beneficial effects on addiction severity, craving, relapse, and mental health in PWUM, compared with Matrix Model treatment, MPH, and control group. Trial registration This study was retrospectively registered in the Iranian website (www.irct.ir) for clinical trials registration (http://www.irct.ir: IRCT20171105037245N1). Registration date: 9 December 2017.