Objectives: To identify the factors associated with re-hospitalization of heart failure (HF) patients at a tertiary care cardiac center in Karachi, Pakistan. Methodology: This cross-sectional study was conducted at the emergency department of the National Institute of Cardiovascular Diseases (NICVD), Karachi, Pakistan, from February 2021 to August 2021. A total of 307 adult patients, aged ≥18 years, diagnosed with HF of any etiology for at least 4 weeks, were included. Patients were assessed for socio-demographics, risk profiles, and various reasons for re-hospitalization. Data was recorded using a pre-designed questionnaire by the researcher and analyzed with SPSS version 23. Results: The mean age of the patients was 59.20±13.27 years, with the majority being male (66.8%). The most common reason for re-hospitalization was non-compliance with treatment (42.7%), followed by lack of regular follow-up (39.4%). Additionally, 28.3% of patients showed non-adherence to fluid intake, and 29% presented with myocardial ischemia. Significant associations were found between 90-day readmission and non-adherence to fluid restriction (p=0.046) as well as lack of regular follow-up (p=0.024). Conclusion: Re-hospitalization of HF patients is primarily associated with non-compliance with medication, lack of regular follow-up, non-adherence to fluid restriction, and myocardial ischemia. Enhanced patient counseling on treatment adherence and lifestyle modifications is essential to reduce the rate of HF-related re-hospitalizations.