Background: Prescription errors in substitution therapy for addiction treatment, including opioid substitution therapy (OST) with methadone and buprenorphine and pharmacotherapy for alcohol use disorder (AUD) with naltrexone, acamprosate, and disulfiram, pose a critical patient safety issue. These errors are a major contributing factor to adverse drug events (ADEs), poor treatment adherence, discontinuation, and severe outcomes such as fatal overdoses. Additional factors such as miscommunication, inadequate training, and complex medication regimens exacerbate the risk. Aim: This systematic review aims to evaluate the prevalence, causes, and consequences of prescription errors in substitution therapy for addiction treatment. It explores the roles of healthcare professionals, system-level factors and their impact on patient safety, focusing on adherence, treatment outcomes, and ADEs. Methodology : A systematic search was conducted in PubMed, Scopus, and Google Scholar for studies published between January 2000 and July 2025. Studies addressing prescription errors in OST or AUD pharmacotherapy, including generic or therapeutic substitution, were included. Data on error types, prevalence, contributing factors, consequences, and interventions were extracted. Qualitative data underwent thematic analysis, while quantitative data were synthesized descriptively. Results: Prescription error rates in OST varied widely, from 1.7% in older adults to 30.3% in overdose reports, with methadone and buprenorphine implicated most frequently. Common errors included incorrect dosing, dispensing errors, and inadequate monitoring, leading to respiratory depression, overdose, and treatment failure. Key contributing factors were miscommunication, insufficient training, frequent formulary changes, and patient-related factors such as cognitive impairment. Pharmacist-led interventions, digital prescribing systems, and standardized protocols significantly reduced errors. Data on AUD pharmacotherapy errors were sparse, highlighting a critical research gap. Conclusion: Prescription errors in substitution therapy pose significant risks to patient safety, primarily due to systemic and human factors. Enhanced training, standardized protocols, and digital tools are effective mitigation strategies. Further research is needed to quantify errors in AUD pharmacotherapy and develop targeted interventions.