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Introduction One of the most important outcomes of diabetes care and treatment is an improvement in patients’ health-related quality of life (HRQoL). Objective This study aimed to review the empirical evidence regarding the predictors of HRQoL among adults with type 2 diabetes mellitus (T2DM). Methods To find all English-language articles published between 2012 and 2022, a comprehensive literature search was conducted using ProQuest, Scopus, PubMed, Science Direct, and CORE. Cross-sectional studies were the focus of this analysis. Search terms included “type 2 diabetes” OR “T2DM” AND “health-related quality of life” OR “HRQoL” AND (“predicting factors” OR “influencing factors” OR “associated factors”). The original search yielded a total of 1,089 studies, from which 35 met the review's inclusion criteria. The systematic review protocol was registered with PROSPERO CRD42023431229. Results The final analysis comprised 24,346 people with type 2 diabetes and used data from 35 cross-sectional studies conducted during the preceding decade. Socio-demographic factors (age, marital status, gender, monthly income, education, area of residence, and religiosity), patient-centered factors (diabetes knowledge and self-efficacy), disease characteristics (comorbidities, duration of diabetes, and insulin treatment), self-management behaviors (physical activity, medication adherence, and frequent glucose checks), and family support were found to be predictors of HRQoL. Conclusion A diabetes program to enhance the HRQoL among people with T2DM is highly encouraged to address these factors, which can be focused on promoting self-management behaviors, diabetes distress management, and encourage family support.