Background: Methamphetamine (METH) dependence is an increasing public health problem with a wide range of mental and physical adverse effects. Recent studies report that oxytocin (OXT) has potential therapeutic properties in drug dependence. Hence, the present study was designed to evaluate the effects of OXT on craving, mental health (depression and anxiety), and stress hormones (ACTH and cortisol) in METH-dependent patients undergoing matrix treatment model (MTM), an intensive outpatient approach for stimulant abuse treatment. Methods: This randomized placebo-controlled clinical trial was conducted in 42 METH-dependent patients undergoing MTM to receive either intranasal OXT 40 IU (n = 21) or normal saline as placebo (n = 21) for 4 weeks. Clinical and biochemical parameters were measured at baseline and end of trials in METH-dependent patients. Results: Our findings indicated that OXT administration for 4 weeks is associated with a significant improvement in the craving and depression scores, respectively (p < 0.001 and p < 0.001), but there was no significant difference for anxiety scores compared with the placebo group. In addition, OXT administration significantly decreased cortisol (p < 0.001) and ACTH levels (p < 0.002). Conclusions: These findings suggest that OXT can be considered as a new potential therapeutic for the treatment of METH-dependent patients undergoing MTM. Further studies are required to explore the effectiveness and safety of OXT.