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Background: Medication adherence among tuberculosis patients is influenced by multiple behavioral, social, and healthcare-related factors. In many developing regions, challenges related to patient knowledge, family involvement, treatment perceptions, and healthcare education continue to affect the success of tuberculosis treatment programs. Understanding the determinants of medication adherence is therefore essential for improving treatment outcomes and strengthening tuberculosis control strategies at the community level. Objective: This study aimed to identify the determinants of medication adherence among patients with tuberculosis in Ogan Komering Ulu, Indonesia. Methods: This study employed a descriptive analytic design with a cross-sectional approach conducted at the UPTD Puskesmas Tanjung Agung, Ogan Komering Ulu Regency, South Sumatra, Indonesia. The study population consisted of all tuberculosis patients registered in the TB treatment program between January and August 2025. A total sampling technique was used, resulting in 44 respondents participating in the study. Data were collected using structured interviews with a questionnaire measuring patient knowledge, family support, perceptions of anti-tuberculosis drug side effects, quality of health education provided by healthcare workers, and medication adherence. Data analysis included univariate analysis to describe variable distributions and bivariate analysis using the Chi-square test. Results: The results showed that 72.7% of respondents were adherent to anti-tuberculosis medication, while 27.3% were non-adherent. Bivariate analysis revealed that patient knowledge (p = 0.003), family support (p < 0.001), perception of drug side effects (p = 0.001), and quality of health education provided by healthcare workers (p < 0.001) were significantly associated with medication adherence. Patients with good knowledge, supportive family environments, positive perceptions of medication side effects, and high-quality educational support from healthcare providers demonstrated higher adherence rates during tuberculosis treatment. Conclusion: Medication adherence among tuberculosis patients is significantly influenced by knowledge, family support, perceptions of medication side effects, and the quality of healthcare education. Strengthening patient education, promoting family involvement in treatment supervision, and improving communication between healthcare providers and patients may enhance adherence behavior and improve tuberculosis treatment outcomes.