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Background: Health-related Quality of life (HRQoL) assessment is essential for optimizing patient care, treatment adjustments, and medical decision-making, particularly in post-Myocardial Infarction (MI) patients, but limited data exists on HRQOL post-MI from Pakistan. This study aimed to assess HRQoL and its determinants in the Pakistani population., Methods: A single-center cross-sectional study was conducted at a tertiary care hospital in Karachi, Pakistan. Patients ≥ 18 years old with a primary diagnosis of acute MI (ICD-9 codes: 410.0-410.9 and ICD-10 codes: 121.0-121.9) discharged from the Cardiology Service from January 2019 to December 2020 who could be contacted and consented to participate were included. Data was collected from electronic records, and patients were interviewed via phone calls using a validated Urdu version of the WHOQOL-BREF questionnaire. Statistical analysis was performed using non-parametric tests via RStudio (Version 1.4.1717)., Results: The final study cohort was 440 patients with a median age of 63.0 (IQR: 56.0,72.0) years, with a male predominance (68.2%). Physical health was the most affected domain. Females, lower-income individuals, and those with lower levels of education had lower HRQoL scores in all domains. Diabetes and the presence of multiple co-morbidities were associated with lower HRQoL. Marital and socioeconomic status, along with psychosocial factors were significantly associated with HRQoL scores. Notably, 62.0% of post-MI patients rated their overall HRQoL as good (4-5 on a Likert scale of 1-5). Cronbach's alpha values indicated good internal consistency, with an overall Cronbach's alpha of 0.902., Conclusion: Although a significant proportion of patients in our cohort reported good HRQoL post-MI, several social factors were associated with lower HRQoL. These factors must be investigated further in discharge planning and post-discharge of patients with MI., Competing Interests: Declarations. Ethics approval and consent for participation & publication: Ethical approval was taken from the Ethics Review Committee (ERC) of Aga Khan University (AKU); ERC reference number: 2023-7040-23790. Eligible patients identified through electronic medical record review were contacted via phone and verbal consent was obtained for participants in the study. Use of verbal consent and study protocol was approved by local ethic review committee. A structured consent form was used for all interviewees, ensuring that all participants received the same information about the study, which helped standardize the consent process and improve the consistency and ethical rigor of the data collection. Any published data will not include identifiable information for any patient. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)