Background Diabetic macular edema (DME) is becoming one of the leading causes of blindness worldwide with a significant impact on quality of life. The effectiveness of intravitreal (IVT) anti-vascular endothelial growth factor (VEGF) therapy has been established by clinical trials and has become the treatment of choice in the majority of DME patients in reducing macular edema and improving visual acuity. Frequent drop-out and discontinuation of treatment are major issues. Lack of compliance can lead to worsening outcomes and be a burden to patients and the healthcare system. Purpose The purpose of this study is to assess multiple factors that affect adherence to IVT anti-VEGF treatment among patients with DME, including socioeconomic causes and the Health Belief Model (HBM) domains, in addition to exploring the relationship between them. Methods This cross-sectional study was conducted among DME patients in Hospital Canselor Tuanku Muhriz, Kuala Lumpur, Malaysia, from December 2020 to June 2021. We identified eligible patients using a retrospective chart review of clinical findings and optical coherence tomography (OCT) findings. Included subjects were of Malaysian nationality, aged 18 years and above, who were initiated or re-initiated IVT anti-VEGF treatment regime and on follow-up for at least six months from initial injection from January 2019 onwards. A translated and validated self-administered questionnaire was given to the respondents. Data were analyzed using IBM SPSS Statistics for Windows, Version 26.0 (Released 2019; IBM Corp., Armonk, New York, United States). Demographics of the patient were summarized using descriptive statistics, independent sample t-test was used to compare the difference in components of the HBM questionnaire. Linear regression was further used to explore the relationship between patients' demographics and the HBM component. Results A total of 141 patients participated in this study, of whom 56.2% patients were adherent to treatment. The majority were aged 60 years and above (56.7%), male (52.5%), Malay (38.9%), and married (71.6%). There was a significant statistical difference in patients who were adherent to treatment, in terms of life entourage (p=0.004, Fisher Exact test). HBM domains that influenced adherence to treatment included perceived severity, perceived barriers, perceived benefits, cues to action, and self-efficacy (p<0.05, independent sample t-test). Further, multiple logistic regression tests on sociodemographic factors and HBM domains after eliminating confounding factors narrowed down the significant variables to perceived susceptibility (p= 0.023), perceived benefits (p< 0.001), and self-efficacy (p< 0.001). Conclusion Patients' adherence to IVT anti-VEGF is influenced by perceived susceptibility to complications from DME, perceived benefits to the treatment, and self-efficacy.