Aims: Health-Related Quality of Life (HRQoL) has been increasing attention in health outcome studies. Factors that individually influence HRQoL, diabetes self-care behaviors, and medication adherence have been widely investigated; however, most previous studies have not tested an integrated association between multiple health outcomes. The purpose of this study was to formulate a hypothetical structural equation model linking HRQoL, diabetes distress, diabetes self-care activities, medication adherence and diabetes-dependent QoL in patients with Type 2 Diabetes Mellitus (T2DM). Methods: A cross-sectional study design was employed, and 497 patients with T2DM were recruited from outpatient clinics in three public hospitals and one government clinic. The patients completed a series of questionnaires. The hypothetical model was tested using Structural Equation Modeling (SEM) analysis. Results: The values of the multiple fit indices indicated that the proposed model provided a good fit to the data. SEM results showed that medication adherence (MMAS) had a significant direct effect on diabetes distress (PAID) (Beta = -0.20). The self-care activities (SDSCA) construct was significantly related to PAID (Beta = -0.24). SDSCA was found to have a significant relationship with HRQoL (SF-36) (Beta = 0.11). Additionally, diabetes distress had a significant effect (Beta = -0.11) on HRQoL of patients. Finally, ADDQoL had a significant effect on HRQoL (Beta = 0.12). Conclusions: The various health outcome indicators such as self-care behaviors, diabetes distress, medication adherence and diabetes-dependent QoL need to be considered in clinical practice for enhancing HRQoL in those patients.