Background: Methadone-induced sexual dysfunction in men can significantly impair their quality of life and reduce methadone adherence, thereby interfering with its therapeutic benefits. Objectives: This study aimed to compare the effects of bupropion and amantadine on reducing sexual dysfunction in methadone-dependent males. Methods: This clinical trial included 47 methadone-dependent males attending the Addiction Treatment Center in Babol, Iran. Participants were randomly assigned to either the amantadine group (n = 23) or the bupropion group (n = 24). Demographic data and addiction history were collected using a checklist, and sexual dysfunction was assessed with the International Index of Erectile Function (IIEF) Questionnaire before and after the intervention. Paired t-tests, independent t-tests, and chi-squared tests were used to compare the two groups. Results: Both groups had similar demographic variables and sexual function scores before the intervention (P > 0.05). However, there was a significant difference between the two groups in terms of total sexual dysfunction scores (52.13 ± 13.07 for bupropion vs. 60.79 ± 4.47 for amantadine; P = 0.006). Additionally, significant differences were observed in sexual desire (P = 0.003), satisfaction with intercourse (P = 0.001), and overall satisfaction (P = 0.034), with higher scores in the bupropion group. Adverse medication-related effects were less prevalent in the bupropion group (54.2%) compared to the amantadine group (60.9%). Conclusions: Bupropion appears to be more effective in improving sexual function in methadone-dependent males undergoing methadone treatment, with patients in the bupropion group achieving better scores than those in the amantadine group. Additionally, the occurrence of adverse effects was lower in the bupropion group compared to the amantadine group.