Introduction: In cases of methadone intoxication, the drug is mainly processed by the liver, however, its elimination through the kidneys is also crucial. On the other hand, naloxone therapy is a gold standard treatment for opioid intoxication, the addition of other drugs can improve its benefits and reduce side effects. Objectives: This study aimed to assess the effectiveness of adding silymarin to the standard treatment of naloxone in patients with methadone intoxication, to improve patient outcomes and reduce the risk of complications associated with alone naloxone therapy. Patients and Methods: This clinical trial study aimed to investigate the efficacy of silymarin in combination with standard treatment for methadone intoxication patients. The study employed a control group, which received standard treatment with naloxone, and an intervention group, which received both naloxone and silymarin. Liver functional tests (LFTs), kidney functional tests, malondialdehyde (MDA), and ferric-reducing ability of plasma (FRAP) were measured at admission and post-intervention times to compare the outcomes between the two groups. Statistical analyses, including chi-square, independent and paired t tests, Wilcoxon, and Mann-Whitney tests were conducted to identify significant differences between the groups. Results: Results indicated that 32 and 33 patients were included in the naloxone and naloxone + silymarin groups, respectively. The results showed that the changes in kidney functional tests such as blood urea nitrogen (BUN) and creatinine (Cr), MDA, and FRAP were not statistically significant between the two groups. However, the changes in LFTs, including, aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP), were statistically significant. Notably, the LFT changes were more pronounced in the group receiving both naloxone and silymarin, indicating a greater reduction in liver enzymes in this combined treatment group. Conclusion: The addition of silymarin to standard naloxone treatment for methadone intoxication patients could improve liver function, as the combined therapy showed a more pronounced reduction in liver enzyme levels compared to standard treatment alone; however, this combination treatment could not change the kidney function and oxidative stress markers. Trial Registration: The trial protocol was approved by the Iranian Registry of Clinical Trials (identifier: IRCT20210216050377N1; ethical code from Shahrekord University of Medical Sciences; IR.SKUMS.REC.1400.048). This study was also registered in Research Registry website with Unique Identifying Number (UIN) of researchregistry10395.