Background: Methadone maintenance therapy (MMT) is a well-established treatment for opioid use disorder, improving retention and reduces relapse. However, treatment outcomes vary significantly on the basis of demographic factors such as age, gender, ethnicity, education, employment status, and genetic variations. Understanding these influences is crucial for optimizing methadone dosing strategies and enhancing patient retention. Objectives: This systematic review evaluated the impact of demographic factors on methadone treatment retention and adherence. Specifically, it examines how age, gender, education level, employment status, ethnicity, and genetic variations influence methadone dosage requirements, treatment dropout rates, and long-term adherence. Methods: A systematic review of 21 peer-reviewed studies published between 2017 and 2024 was conducted. Databases including PubMed, Scopus, and Web of Science were searched for relevant literature. Studies that quantitatively or qualitatively analyzed demographic influences on methadone treatment outcomes were included. A thematic synthesis identified patterns in treatment retention and dosage requirements across different demographic groups. Results: Findings indicate that younger patients (<30 years) have a 2.1× higher dropout rate than older individuals do. Males generally tolerate higher methadone doses (mean: 80 mg/day vs. 65 mg/day in females) and show better retention, whereas females express greater concerns about dependency and are 1.26× more likely to discontinue treatment. Patients with higher education levels showed improved adherence, with a non-adherence rate of 37.4% vs. 52.2% for those with lower education levels (p < 0.05). Employment positively correlated with retention (OR = 1.5). Ethnicity and genetic variations affect methadone metabolism, with CYP2B6*6 carriers requiring 30% lower doses and OPRM1 polymorphisms influencing retention rates. Higher methadone doses (≥60 mg/day) significantly improved retention (HR = 0.44, 95% CI: 0.31–0.62). Conclusions: Demographic factors significantly impact methadone treatment outcomes, highlighting the need for personalized dosing strategies and targeted interventions. The incorporation of genetic screening, socioeconomic support, and sex-specific approaches may increase treatment efficacy and reduce disparities. Future research should further explore these factors to refine methadone treatment protocols and improve patient-centered care.